Early administration of low-dose colchicine after myocardial infarction

ABSTRACT

The invention relates to colchicine for use in a method of treating a patient after having a myocardial infarction (MI), the method including initiating the administration of colchicine at a daily low dose to the patient within about 3 days of the MI.

BACKGROUND OF THE INVENTION

The invention relates to a treatment regimen for patients aftersuffering a myocardial infarction.

Inflammation appears to play an important role in atherosclerosis(Hansson G K, Inflammation, atherosclerosis, and coronary arterydisease. N Engl J Med 2005; 352:1685-95). Inhibition of interleukin-1βby the injectable monoclonal antibody canakinumab led to a 15% lowerrisk of cardiovascular events than was observed with placebo in theCanakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) but alsoled to a slightly higher incidence of fatal infections (Ridker P M etal., Antiinflammatory therapy with canakinumab for atheroscleroticdisease. N Engl J Med 2017; 377:1119-31). In contrast, methotrexate didnot affect cardiovascular outcomes or plasma markers of inflammation inthe Cardiovascular Inflammation Reduction Trial (CIRT) (Ridker P M etal., Low-dose methotrexate for the prevention of atherosclerotic events.N Engl J Med 2019; 380:752-62). Considering these differing results andgiven that canakinumab is not clinically available for cardiovascularprevention, the search for a widely used alternative antiinflammatorytreatment that may reduce the risk of atherosclerotic events amongpatients with coronary artery disease continues.

Colchicine is an inexpensive, orally administered, potentanti-inflammatory medication that was initially extracted from theautumn crocus and has been used for centuries. Its mechanism of actionis through the inhibition of tubulin polymerization and microtubulegeneration and, possibly, effects on cellular adhesion molecules,inflammatory chemokines, and the inflammasome (Ravelli R B et al.,Insight into tubulin regulation from a complex with colchicine and astathmin-like domain. Nature 2004; 428:198-202; Perico N et al.,Colchicine interferes with L-selectin and leukocyte function-associatedantigen-1 expression on human T lymphocytes and inhibits T cellactivation. J Am Soc Nephrol 1996; 7:594-601; Pope R M and Tschopp J,The role of interleukin-1 and the inflammasome in gout: implications fortherapy. Arthritis Rheum 2007; 56:3183-8). Colchicine is currentlyindicated for the treatment of gout, familial Mediterranean fever, andpericarditis (Cerquaglia C et al., Pharmacological and clinical basis oftreatment of Familial Mediterranean Fever (FMF) with colchicine oranalogues: an update. Curr Drug Targets Inflamm Allergy 2005; 4:117-24;and Imazio M et al., Colchicine in addition to conventional therapy foracute pericarditis: results of the COlchicine for acute PEricarditis(COPE) trial. Circulation 2005; 112:2012-6).

In the Low-Dose Colchicine (LoDoCo) trial, patients with stable coronarydisease treated with colchicine at a dose of 0.5 mg once daily had fewercardiovascular events than those not receiving colchicine (Nidorf S M etal., Low-dose colchicine for secondary prevention of cardiovasculardisease. J Am Coll Cardiol 2013; 61:404-10). However, that trialenrolled only 532 patients and was not placebo-controlled.

Because acute coronary syndromes are associated with higher risks ofrecurrent events and exacerbated inflammation a need exists in the artfor new treatment regimens.

SUMMARY OF THE INVENTION

A clinical trial referred to as the Colchicine Cardiovascular OutcomesTrial (COLCOT) was conducted to evaluate the effects of colchicine oncardiovascular outcomes as well as its long-term safety profile inpatients who had recently had a myocardial infarction.

The results of the COLCOT trial support that the use of colchicine inpatients who have recently had a myocardial infarction significantlyimproved their quality of life in several ways. Colchicine at a dailylow dose of 0.5 mg led to a statistically significant lower risk ofischemic cardiovascular events than placebo. Death from cardiovascularcauses, resuscitated cardiac arrest, myocardial infarction, stroke, andurgent hospitalization for angina leading to coronary revascularizationwas also significantly lower among the patients who received 0.5 mg ofcolchicine than those who received placebo. Patients receiving low dosecolchicine had reduced morbidity relative to placebo, as is demonstratedby the rates of the respective primary composite end points for the twopatient populations (P=0.02). This reduction in morbidity wasparticularly prominent among colchicine-receiving patients in thereduction of severe conditions, such as stroke and urgenthospitalization for angina leading to revascularization: hazard ratiosare 0.26 (95% confidence interval is 0.10-0.70) and 0.50 (95% confidenceinterval is 0.31-0.81), respectively. Still further, unlike the use ofthe anti-inflammatory canakinumab for atherosclerotic events, colchicinedid not increase the incidence of septic shock. Moreover, no seriousadverse event of myopathy linked to colchicine occurred despite the useof statins in 99% of trial participants.

The results of the COLCOT trial have been further analyzed to determineif time to treatment initiation (TTI) had any effect on the outcome ofthe treatment. Three different cutoffs for TTI were used in order todetermine the association between early initiation of therapy andclinical outcomes. These cutoffs were determined based on the usualjourney of patients with MI. The first 30-day post-MI timeline wasdivided into three independent periods of time, and analyzed as such:from day 0 to 3, referring to in-hospital management; from day 4 to 7,referring to early post-discharge period and from day 8 to 30, referringto late post-discharge period.

The main COLCOT results revealed that colchicine reduced the risk ofischemic CV events by 23% in the post-MI setting. Results from thepresent TTI analysis support that early suppression of inflammationafter MI provides even greater benefits, with a reduction of 48% in therisk of the composite primary endpoint when colchicine was initiatedbetween days 0 and 3. The demonstrated cost-effectiveness of low-dosecolchicine also supports its large-scale use after MI. Results of theLoDoCo2 study of patients with stable coronary artery disease complementthose of COLCOT in the post-MI setting.

In view of the aforementioned, the invention, in one aspect, relates tocolchicine for use in a method of treating a patient alter having amyocardial infarction (MI), the method comprising initiating theadministration of colchicine at a daily low dose to the patient withinabout 3 days of the MI.

In another aspect, the invention relates to a colchicine for use in amethod of treating a patient after having a MI; the method comprisinginitiating the administration of colchicine at a daily low dose to thepatient within about 4 days of the MI.

In another aspect, the invention relates to a colchicine for use in amethod of treating a patient after having a MI; the method comprisinginitiating the administration of colchicine at a daily low dose to thepatient within about 5 days of the MI.

In another aspect, the invention relates to a colchicine for use in amethod of treating a patient after having a MI, the method comprisinginitiating the administration of colchicine at a daily low dose to thepatient within about 30 days of the MI.

In another aspect, the invention relates to a method of treating apatient after having a MI, the method comprising initiating theadministration of colchicine at a daily low dose to the patient withinabout 3 days of the MI.

In another aspect, the invention relates to a method of treating apatient after having a MI, the method comprising initiating theadministration of colchicine at a daily low dose to the patient withinabout 4 days of the MI.

In another aspect, the invention relates to a method of treating apatient after having a MI, the method comprising initiating theadministration of colchicine at a daily low dose to the patient withinabout 5 days of the MI.

In another aspect, the invention relates to a method of treating apatient after having a MI, the method comprising initiating theadministration of colchicine at a daily low dose to the patient withinabout 30 days of the MI.

In another aspect, the invention relates to the use of a daily low doseof colchicine for treating a patient after having a MI, wherein the useis initiated within about 3 days of the MI.

In another aspect, the invention relates to the use of a daily low doseof colchicine for treating a patient after having a MI, wherein the useis initiated within about 4 days of the MI.

In another aspect, the invention relates to the use of a daily low doseof colchicine for treating a patient after having a MI, wherein the useis initiated within about 5 days of the MI.

In another aspect, the invention relates to the use of a daily low doseof colchicine for treating a patient after having a MI, wherein the useis initiated within about 30 days of the MI.

In a further aspect, the invention: relates to the use of colchicine forthe manufacture of a medicament for treating a patient after having aMI, wherein the colchicine is a low dose colchicine for dailyadministration initiated within about 3 days of the MI.

In a further aspect, the invention relates to the use of colchicine forthe manufacture of a medicament for treating a patient after having aMI, wherein the colchicine is a low dose colchicine for dailyadministration initiated within about 4 days of the MI.

In a further aspect, the invention relates to the use of colchicine forthe manufacture of a medicament for treating a patient after having aMI, wherein the colchicine is a low dose colchicine for dailyadministration initiated within about 5 days of the MI.

In a further aspect, the invention relates to the use of colchicine forthe manufacture of a medicament for treating a patient after having aMI, wherein the colchicine is a low dose colchicine for dailyadministration initiated within about 30 days of the MI.

In another aspect, the present invention relates to low-dose colchicinefor use in treating a patient having a MI, wherein the colchicine is fordaily administration initiated within about 3 days of the MI.

In another aspect, the present invention relates to low-dose colchicinefor use in treating a patient having a MI, wherein the colchicine is fordaily administration initiated within about 4 days of the MI.

In another aspect, the present invention relates to low-dose colchicinefor use in treating a patient having a MI, wherein the colchicine is fordaily administration initiated within about 5 days of the MI.

In another aspect, the present invention relates to low-dose colchicinefor use in treating a patient having a MI, wherein the colchicine is fordaily administration initiated within about 30 days of the MI.

In some embodiments, the method involves administering colchicine within5 days of the MI (for example, at 1 day, 2 days, 3 days, or 4 days). Insome embodiments, the method includes administering colchicine within 4days of the myocardial infarction (for example, at 1 day, 2 days, or 3days), in still other embodiments, the method includes administeringcolchicine within 3 days of the myocardial infarction (for example, at 1day or 2 days).

In some embodiments, the patient administered colchicine receivedpercutaneous coronary intervention for treating the patient's myocardialinfarction.

In some embodiments, the myocardial infarction is acute MI (AMI). Insome embodiments, the MI is not type 2 MI.

In some embodiments, the patient administered was previously prescribeda medication (for example, an antiplatelet agent, a statin, aspirin or acombination thereof).

In some embodiments, the patient administered is concurrently beingtreated with a medication (for example, an antiplatelet agent, a statin,aspirin, or a combination thereof).

In some embodiments, the patient is at a lower risk of a cardiovascularevent, relative to a patient not being administered colchicine. Forexample, the cardiovascular event is an ischemic cardiovascular event.In some embodiments, the cardiovascular event is cardiovascular death,resuscitated cardiac arrest, myocardial infarction, stroke, or urgenthospitalization for angina requiring coronary revascularization.

In some embodiments, the patient has atherosclerotic coronary arterydisease.

In some embodiments the patient does not have severe heart failure,reduced left ventricular fraction, recent stroke, type 2 MI, plannedcoronary artery bypass by graft (CABG), inflammatory bowel disease orchronic diarrhea.

In another aspect, the invention relates to a method of reducing therisk of or preventing a stroke in a patient after having an MI, themethod comprising initiating the administration of colchicine at a dailylow dose to the patient within about 30 days of an MI.

In some embodiments, the method involves administering colchicine within4-7 days (for example, 5 days, 6 days, or 7 days) of the MI.

In some embodiments, the method involves administering colchicine within3 days of the MI.

In another aspect, the invention relates to the use of a daily low doseof colchicine for reducing the risk of or preventing a stroke in apatient after having a MI, wherein the use is initiated within 30 daysof the MI.

In another aspect, the invention relates to the use of a daily low doseof colchicine for reducing the risk of or preventing a stroke in apatient after having a MI, wherein the use is initiated between 4-7 daysafter the MI.

In some embodiments, the invention relates to the use of a daily lowdoes of colchicine for reducing the risk of or preventing a stroke in apatient after having a MI, wherein the use is initiated within 3 days ofthe MI.

In a further aspect, the invention relates to the use of colchicine forthe manufacture of a medicament for reducing the risk of or preventing astroke in a patient after having a MI, wherein the colchicine is a lowdose colchicine for daily administration initiated within 30 days of theMI.

In a further aspect, the invention relates to the use of colchicine forthe manufacture of a medicament for reducing the risk of or preventing astroke in a patient after having a MI, wherein the colchicine is a lowdose colchicine for daily administration initiated between 4 and 7 daysof the MI.

In another aspect, the present invention relates to the use ofcolchicine for the manufacture of a medicament for reducing the risk ofor preventing stroke in a subject after having a MI, wherein thecolchicine is for daily administration initiated within about 3 days ofthe MI.

In some embodiments, the administration of colchicine is initiated uponassessment in (a) an emergency department (ED), (b) the hospital, or (c)a medical office setting.

In some embodiments, colchicine is administered in the form of a tabletor a capsule (e.g., a coated tablet or capsule). In some embodiment,colchicine is administered in the form of a film-coated tablet.

In some embodiments, colchicine is administered at 0.3 to 0.7 mg. Forexample, colchicine is administered at 0.4 to 0.6 mg, and is preferablyadministered at about 0.5 mg. In some embodiments, colchicine isadministered in a 0.5 mg tablet or a 0.6 mg tablet. In otherembodiments, colchicine is administered in a 0.25 mg tablet.

In some embodiments, colchicine is administrated once, twice, or threetimes daily.

In some embodiments, colchicine is administered once per day.

In some embodiments, the colchicine is administered without pre-loadingthe patient with colchicine (e.g., administering a higher dose, such as1.0 mg per day or higher (1.5 mg or 2.0 mg) in a single or multipledoses, at the onset of the treatment for one, two, or three days beforeswitching to a lower dose of, e.g., 0.5 mg per day, for the remainder ofthe duration of treatment).

In some embodiments, the patient is an adult human (i.e., the patient is18 years old or older).

In another aspect, the invention relates to colchicine for use in amethod of treating a patient after having a myocardial infarction (MI),the method including the administration of colchicine at a daily lowdose to the patient within about 3 days (e.g., 1 day, 2 days, and 3days) of the MI.

Use of colchicine for treating a patient after having a myocardialinfarction typically continues, as needed, throughout the life of apatient. For example, in some embodiments, the duration of treatment isfor 6 months, 12 months, 18 months, 24 months, 30 months, 36 months, oreven longer as is needed. In some embodiments, the duration of thetreatment is for at least about 23 months.

Various colchicine formulations, including film-coated tablets, arereadily available and well known in the art.

Other features and advantages of the invention will be apparent from thefollowing Detailed Description, the Drawings, and the Claims.

Definitions

As used herein, the term “cardiovascular death” refers to deathresulting from a cardiovascular disease, including coronary heartdisease, cerebrovascular disease, peripheral arterial disease, rheumaticheart disease, congenital heart disease, deep vein thrombosis, or apulmonary embolism, or sudden cardiac event, including cardiac arrestand myocardial infarction.

As used herein, the term “myocardial infarction” refers to acardiovascular disorder characterized by localized necrosis resultingfrom obstruction of the blood supply. MI may be classified as an STelevation myocardial infarction (STEW) or Non-ST elevation myocardialinfarction (NSTEMI) based on the results of an ECG. A more explicitclassification system, based on international consensus in 2012, alsoexists. This classifies myocardial infarctions into five types includingtypes 1 and 2. Type-1 AMI is caused by an acute atherothromboticcoronary event; type-2 AMI is a more heterogeneous entity, where acondition other than coronary artery disease (CAD) contributes to anacute imbalance between oxygen supply (e.g., hypoxemia, anemia,hypotension) and demand (e.g., tachycardia, hypertension).

As used herein, the term “resuscitated cardiac arrest” refers an abruptloss of heart function resulting in a loss of blood flow to the bodywhich requires the subject be resuscitated using any method known to oneof skill in the art, including cardiopulmonary resuscitation or adefibrillator.

As used herein, the term “urgent hospitalization for angina requiringcoronary revascularization” refers to an immediate need for a patient tobe hospitalized due to severe chest discomfort felt due to ischemicheart disease which requires surgical intervention grafting and/orstenting approaches to improving blood flow to the heart and relieveangina.

As used herein, the term “stroke” refers to a condition which occurswhen the blood supply to a part of the brain is suddenly interrupted(i.e., ischemic stroke) or when a blood vessel in the brain bursts andreleases blood into the spaces surrounding the brain cells (i.e.,hemorrhagic stroke). The symptoms of a stroke include numbness orweakness, especially on one side of the body corresponding to thecontralateral side of the stroke, confusion, trouble understanding orproducing speech, impaired vision in both eyes, impaired mobility,dizziness, or loss of balance or coordination. Stroke may be diagnosedusing several techniques, such as, e.g., neurological examination, bloodtesting, computed tomography (CT) scan, magnetic resonance imaging (MRI)scan, Doppler ultrasound, and arteriography. Although stroke is adisease of the brain, it can affect the entire body by causing, e.g.,paralysis, cognitive impairment, speech impairment, emotionaldysregulation, and pain.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of a flow chart of the randomization and subjectdisposition of the patients in the Time-to-Treatment study.

FIG. 2 is a graph of the association between the time-to-treatmentinitiation and the adjusted hazard ratio (solid line) with the 95%confidence intervals of the adjusted hazard ratio (dashed line)calculated using a quadratic multivariable Cox regression model.

FIG. 3A is a graph of the cumulative incidence of cardiovascular events(time-to-treatment population). Shown are the Kaplan-Meier event curvesfor the primary efficacy composite end point (a composite ofcardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgenthospitalization for angina requiring coronary revascularization) in thecolchicine group and the placebo group for patients with atime-to-treatment initiation of 3 days. The inset shows the same data onan enlarged y-axis.

FIG. 3B is a graph of the cumulative incidence of cardiovascular events(time-to-treatment population). Shown are the Kaplan-Meier event curvesfor the secondary efficacy composite end point (a composite ofcardiovascular death, resuscitated cardiac arrest, myocardialinfarction, or stroke) in the colchicine group and the placebo group forpatients with a time-to-treatment initiation of days. The inset showsthe same data on an enlarged y-axis.

DETAILED DESCRIPTION OF THE INVENTION

We performed a randomized, double-blind trial involving patientsrecruited within 30 days after a myocardial infarction. The patientswere randomly assigned to receive either low-dose colchicine (0.5 mgonce daily) or placebo. A total of 4745 patients were enrolled; 2366patients were assigned to the colchicine group, and 2379 to the placebogroup. Patients were followed for a median of 22.6 months.

The primary efficacy end point was a composite of death fromcardiovascular causes, resuscitated cardiac arrest, myocardialinfarction (e.g., acute myocardial infraction or type II myocardialinfarction), stroke, or urgent hospitalization for angina leading tocoronary revascularization. The components of the primary end point andsafety were also assessed.

Study Design and Patient Population

COLCOT was an international multicenter, randomized, double-blindedtrial that randomly assigned patients to receive either low-dosecolchicine (0.5 mg once daily) or placebo. The study protocol and mainresults have been published (see, Tardif et al., N Engl J Med 2019).Patients were considered eligible if they had a recent MI (<30 days).Main exclusion criteria were severe heart failure, reduced leftventricular ejection fraction (<35%), recent stroke (<3 months), type 2MI, recent (<3 years) or planned coronary artery bypass graft (CABG),history of cancer (<3 years), and inflammatory bowel disease or chronicdiarrhea. All patients enrolled in the trial benefited from percutaneouscoronary intervention whenever indicated and guidelines-directedmanagement of CV disease prior to randomization (see. Tardif et al., NEngl J Med 2019).

Clinical follow-up consisted of evaluations at 1 and 3 months afterrandomization and every 3 months thereafter. An independent clinicalendpoint committee, blinded to trial-group assignment, adjudicatedclinical endpoints. The trial was locally approved by the variousinstitutional review boards, and all patients signed a written informedconsent before enrollment.

Efficacy Endpoints

The primary efficacy endpoint was a composite of CV death, resuscitatedcardiac arrest, MI, stroke, or urgent hospitalization for anginarequiring coronary revascularization. The secondary endpoints consistedof the components of the primary efficacy endpoint, all-cause death, anda composite of CV death, resuscitated cardiac arrest, MI, or stroke.Exploratory endpoints included all coronary revascularizations,including both elective and urgent coronary revascularizations.

Cutoffs for Time-to-Treatment Initiation (TTI) of Colchicine

Three different cutoffs for TTI were used in order to determine theassociation between early initiation of therapy and clinical outcomes.These cutoffs were determined based on the usual journey of patientswith MI. The first 30-day post-MI timeline was divided into threeindependent periods of time, and analyzed as such: from day 0 to 3,referring to in-hospital management; from day 4 to 7, referring to earlypost-discharge period and from day 8 to 30, referring to latepost-discharge period.

Results Baseline Characteristics for Patients in TTI Analysis

Of the 4745 patients randomized in COLCOT, 4661 were included in the TTIanalysis (colchicine, N=2322; placebo, N=2339) (FIG. 1 ). Overall,patients were randomized at 13.5±10.1 days following the index MI, 25.6%between days 0 and 3, 15.4% between days 4 and 7 and 59.0% at day 8 orafter. Baseline characteristics were similar between the colchicine andplacebo groups (Table 1). Patients were mostly men (81.0%) with a meanage of 60.5 years, 20.2% had diabetes, 51.0% had a history ofhypertension, 29.7% were active smokers, and 16.8% had had a prior PCI.Background therapy included aspirin, a second anti-platelet agent and astatin in 98.8%, 98.0% and 99.0% of patients, respectively. The vastmajority of patients (93.0%) underwent percutaneous coronaryintervention (PCI) during the index hospitalization, with no differencein terms of time to PCI between the two groups.

TABLE 1 Baseline Characteristics according to treatment allocation forTime-to-Treatment Initiation (TTI) All patients Colchicine group Placebogroup Characteristics N = 4661 N = 2322 N = 2339 Age (years) - 60.5 ±10.6 60.6 ± 10.6 60.5 ± 10.6 mean ± SD Male sex - no. (%) 3774 (81.0%)1861 (80.1%) 1913 (81.8%) BMI (kg/m²) - 28.3 ± 4.7  28.2 ± 4.8  28.4 ±4.7  mean ± SD Current Smoking - 1382/4659 (29.7) 694/2322 (29.9%)688/2337 (29.4%) no./total no. (%) History of 2377 (51.0%) 1160 (50.0%)1217 (52.0%) Hypertension - no. (%) History of Diabetes - 942 (20.2%)451 (19.4%) 491 (21.0%) no. (%) Prior MI - no. (%) 751 (16.1%) 360(15.5%) 391 (16.7%) Prior PCI - no. (%) 783 (16.8%) 382 (16.5%) 401(17.1%) Prior CABG - no. 146 (3.1%) 66 (2.8%) 80 (3.4%) (%) Prior HF -no. (%) 90 (1.9%) 48 (2.1%) 42 (1.8%) Prior Stroke or TIA - 119 (2.6%)53 (2.3%) 66 (2.8%) no. (%) PCI associated with 4336 (93.0%) 2154(92.8%) 2182 (93.3%) the index event - no. (%) Medication use - no. (%):Aspirin 4605 (98.8%) 2291 (98.7%) 2314 (98.9%) Other antiplatelet 4567(98.0%) 2267 (97.6%) 2300 (98.3%) agent Statin 4615 (99.0%) 2297 (98.9%)2318 (99.1%) Beta-blocker 4143 (88.9%) 2077 (89.4%) 2066 (88.3%) TTI 0-3days - no. 1193 (25.6%) 604 (26.0%) 589 (25.2%) (%) TTI 4-7 days - no.720 (15.4%) 364 (15.7%) 356 (15.2%) (%) TTT ≥8 days - no. 2748 (59.0%)1354 (58.3%) 1394 (59.6%) (%) Time from index MI 13.5 ± 10.1 13.5 ± 10.113.5 ± 10.0 to randomization (days) - mean ± SD Time from Index MI 1.4 ±2.9 1.4 ± 2.9 1.4 ± 2.9 to PCI (days) - mean ± SD Time from PCI to 11.9± 9.9  11.9 ± 9.9  11.9 ± 9.9  randomization (days) - mean ± SDAbbreviations: CABG, coronary-artery bypass graft surgery; HF, heartfailure; PCI, percutaneous coronary intervention; TIA, transientischemic attack.

Data were missing on the following characteristics: age (assessedaccording to date of birth; see below) for 431 patients (213 in thecolchicine group and 218 in the placebo group) and body-mass index (theweight in kilograms divided by the square of the height in meters) for 5(1 and 4 patients, respectively). Date of birth was not required fieldbecause it was considered in some countries to be sensitive data thatcould allow for the identification of patients.

For statistical reporting, missing information regarding the day ofbirth was replaced by 15, and missing information regarding the monthand day of birth was replaced by July 1.

Baseline characteristics according to TTI strata are shown in Table 2.Patients in whom therapy was initiated between days 0 and 3, whencompared to those at days 8 to 30, were younger (59.1±10.8 vs. 61.3±10.4years) and more often active smokers (43.8 vs. 20.2%), had less commonlyhypertension (41.1 vs. 56.2%) and diabetes (17.4 vs. 22.0%) butunderwent more often PCI associated with the index MI (95.8 vs. 91.3%),all p<0.05.

TABLE 2 Baseline characteristics according to TTI TTI 0-3 days TTI 4-7days TTT ≥8 days Characteristics N = 1193 N = 720 N = 2748 p* p ** Age(years) - mean ± 59.1 ± 10.8 60.1 ± 11.0 61.3 ± 10.4 <0.0001 <0.0001 SDMale sex - no. (%) 980 (82.2%) 605 (84.0%) 2189 (80.0%) 0.014 0.071 BMI(kg/m²) - mean ± SD 28.1 ± 4.6  27.7 ± 4.6  28.6 ± 4.8  <0.0001 0.004Current Smoking - no. 522 (43.8%) 306 (42.6%) 554 (20.2%) <0.0001<0.0001 (%) History of Hypertension - 490 (41.1%) 343 (47.6%) 1544(56.2%) <0.0001 <0.0001 no. (%) History of Diabetes - no. 208 (17.4%)130 (18.1%) 604 (22.0%) 0.001 0.001 (%) Prior MI - no. (%) 170 (14.3%)111 (15.4%) 470 (17.1%) 0.070 — Prior PCI - no. (%) 182 (15.3%) 107(14.9%) 494 (18.0%) 0.035 0.037 Prior CABG - no. (%) 34 (2.9%) 30 (4.2%)82 (3.0%) 0.218 — Prior HF - no. (%) 14 (1.2%) 12 (1.7%) 64 (2.3%) 0.0460.017 Prior Stroke or TIA - no. 20 (1.7%) 21 (2.9%) 78 (2.8%) 0.084 —(%) PCI associated with the 1143 (95.8%) 685 (95.1%) 2508 (91.3%)<0.0001 <0.0001 index event - no. (%) Medication use - no. (%): Aspirin1181 (99.0%) 715 (99.3%) 2709 (98.6%) 0.219 — Other antiplatelet agent1177 (98.7%) 708 (98.3%) 2682 (97.6%) 0.072 — Statin 1188 (99.6%) 708(98.3%) 2719 (98.9%) 0.024 0.047 Beta-blocker 1093 (91.6%) 642 (89.2%)2408 (87.6%) 0.001 0.0003 Time from index MI to 2.1 ± 0.8 5.1 ± 1.1 20.8± 6.6  <0.0001 <0.0001 randomization (days) - mean ± SD Time from IndexMI to 0.4 ± 0.7 1.4 ± 1.8 1.8 ± 3.6 <0.0001 <0.0001 PCI (days) - mean ±SD Time from PCI to 1.6 ± 0.9 3.7 ± 1.9 18.8 ± 7.3  <0.0001 <0.001randomization (days) - mean ± SD Abbreviations: CABG, coronary-arterybypass graft surgery; HF, heart failure; PCI, percutaneous coronaryintervention; TIA, transient ischemic attack. Data were missing on thefollowing characteristics: age (assessed according to date of birth; seebelow) for 431 patients (213 in the colchicine group and 218 in theplacebo group) and body-mass index (the weight in kilograms divided bythe square of the height in meters) for 5 (1 and 4 patients,respectively). Date of birth was not a required field because it wasconsidered in some countries to be sensitive data that could allow forthe identification of patients. For statistical reporting, missinginformation regarding the day of birth was replaced by 15, and missinginformation regarding the month and day of birth was replaced by July 1.*Group comparison TTI 0-3 vs. TTI 4-7 vs. TTI ≥8 days **Group comparisonTTI <3 vs. TTI ≥8 days

Effects of Time-to-Treatment Initiation on the Primary Efficacy Endpoint

The effects of colchicine on the primary endpoint according to TTI areshown in Table 3 and FIG. 2 . A primary endpoint event occurred in 4.3%of patients in the colchicine group, as compared to 8.3% of those in theplacebo group when TTI was between days 0 and 3 (N=1193, HR=0.52, 95% CI0.32-0.84, p=0.007, FIG. 3A). Corresponding rates were 6.0 and 5.9% whenTTI was between days 4 and 7 (N=720) and 5.7 and 7.1% when TTI was onday 8 or after (N=2748), but these differences between groups did notreach statistical significance. Table 3 also shows the percentages ofpatients with events and the hazard ratios for the components of theprimary endpoint, including CV death (HR=1.04, 95% CI 0.15-7.37),resuscitated cardiac arrest (HR=0.33, 95% CI 0.03-3.20), MI (HR=0.58,95% CI 0.32-1.05), stroke (HR=0.21, 95% CI 0.02-1.81) and urgenthospitalization for angina requiring coronary revascularization(HR=0.35, 95% CI 0.14-0.88).

TABLE 3 Efficacy endpoints according to TTI (N = 4661, colchicine vs.placebo) TTI 0-3 days, N = 1193 TTI 4-7 days, N = 720 TTI ≥ 8 days, N =2748 Colchicine vs. placebo Colchicine vs. placebo Colchicine vs.placebo no. (%) no. (%) no. (%) Endpoints HR (95% CI); p HR (95% CI); pHR (95% CI); p Primary composite 26 (4.3%) vs. 49 (8.3%) 22 (6.0%) vs.21 (5.9%) 77 (5.7%) vs. 99 (7.1%) endpoint 0.52 (0.32-0.84); p = 0.0070.96 (0.53-1.75); p = 0.896 0.82 (0.61-1.11); p = 0.200 CV death 2(0.3%) vs. 2 (0.3%) 2 (0.5%) vs. 4 (1.1%) 15 (1.1%) vs. 18 (1.3%) 1.04(0.15-7.37); p = 0.970 0.45 (0.08-2.46); p = 0.356 0.89 (0.45-1.76); p =0.734 Resuscitated cardiac 1 (0.2%) vs. 3 (0.5%) 2 (0.5%) vs. 1 (0.3%) 2(0.1%) vs. 2 (0.1%) arrest 0.33 (0.03-3.20); p = 0.340 1.90(0.17-20.95); p = 0.600  1.02 (0.14-7.22); p = 0.986 MI 17 (2.8%) vs. 29(4.9%) 16 (4.4%) vs. 9 (2.5%)  52 (3.8%) vs. 59 (4.2%) 0.58 (0.32-1.05);p = 0.071 1.67 (0.74-3.78); p = 0.218 0.93 (0.64-1.35); p = 0.710 Stroke1 (0.2%) vs. 5 (0.8%) 1 (0.3%) vs. 3 (0.8%)  2 (0.1%) vs. 11 (0.8%) 0.21(0.02-1.81); p = 0.156 0.28 (0.03-2.71); p = 0.272 0.19 (0.04-0.84); p =0.029 Urgent hospitalization   6 (1%) vs. 17 (2.9%) 4 (1.1%) vs. 6(1.7%) 15 (1.1%) vs. 26 (1.9%) for angina requiring 0.35 (0.14-0.88); p= 0.026 0.63 (0.18-2.24); p = 0.476 0.61 (0.32-1.16); p = 0.131 coronaryrevascularization Secondary Composite 20 (3.3%) vs. 36 (6.1%) 18 (4.9%)vs. 16 (4.5%) 67 (4.9%) vs. 77 (5.5%) Endpoint 0.55 (0.32-0.95); p =0.031 1.04 (0.53-2.03); p = 0.919 0.92 (0.66-1.28); p = 0.629 All-causedeath 6 (1.0%) vs. 6 (1.0%) 8 (2.2%) vs. 7 (2.0%) 26 (1.9%) vs. 31(2.2%) 1.03 (0.33-3.19); p = 0.962 1.03 (0.37-2.84); p = 0.957 0.90(0.53-1.51); p = 0.684 All Coronary 33 (5.5%) vs. 51 (8.7%) 25 (6.9%)vs. 18 (5.1%) 72 (5.3%) vs. 94 (6.7%) Revascularizations 0.63(0.40-0.97); p = 0.037 1.41 (0.76-2.61); p = 0.275 0.81 (0.59-1.10); p =0.172

The effects of colchicine on the primary endpoint for a TTI of less than4 days is shown in Table 4 and Table 5. The effects of colchicine on theprimary endpoint for a TTI of less than 5 days is shown in Table 6 andTable 7. Both the TTI of less than 4 days and the TTI of less than 5days was were calculated using a basic model (Table 4 and Table 6) aswell as an adjusted model (Table 5 and Table 7) which is described belowin the statistical analysis section. In all cases, the interactionp-value was not significant (p>0.05), meaning that the conclusion overPlacebo vs. Colchicine group can be obtained directly from therespective p-values for HR. In other words, relationships within theplacebo and colchicine groups with TTI are both linear/parallel and theinterpretation is straightforward. For a TTI of 4 days or less,colchicine was shown to offer additional protection over the placebo inboth the basic (Table 4 and Table 6) and the adjusted models (Table 5and Table 7). The adjusted models resulted in a hazard ratio (HR) of0.58 and a p value of 0.0126.

TABLE 4 Effect of Colchicine with TTI of <4 days calculated using basicmodel POSITIVELY DELAY BETWEEN ADJUDICATED RANDOMIZATION PRIMARY PlaceboColchicine All AND INDEX MI ENDPOINT N = 2339 N = 2322 N = 4661  [0-4]days N 712 768 1480 Yes 54 (7.6%) 34 (4.4%) 88 (5.9%) No 658 (92.4%) 734(95.6%) 1392 (94.1%) [5-30] days n 1627 1554 3181 Yes 115 (7.1%) 91(5.9%) 206 (6.5%) No 1512 (92.9%) 1463 (94.1%) 2975 (93.5%) CoxRegression Model for Time to First Positively Adjudicated PrimaryEndpoint Including Treatment Group. Delay between randomization andindex MI and Delay between randomization and index MI × Randomizedtreatment group interaction Interaction Effect p-value Delay betweenrandomization and index 0.1501 MI × Randomized intermittent group Delaybetween randomization and index MI Effect HR (95% CI) p-value  [0-4]days Colchicine vs. placebo 0.57 (0.37; 0.87) 0.0098 [5-20] daysColchicine vs. placebo 0.83 (0.63; 1.09) 0.1739 Notes: Model based on N= 4661 observations. Deaths of undetermined cause were classified as CVdeaths.

TABLE 5 Effect of Colchicine with TTI of <4 days calculated usingadjusted model POSITIVELY DELAY BETWEEN ADJUDICATED RANDOMIZATIONPRIMARY Placebo Colchicine All AND INDEX MI ENDPOINT N = 2339 N = 2322 N= 4661  [0-4] days N 712 768 1480 Yes 54 (7.6%) 34 (4.4%) 88 (5.9%) No658 (92.4%) 734 (95.6%) 1392 (94.1%) [5-30] days n 1627 1554 3181 Yes115 (7.1%) 91 (5.9%) 206 (6.5%) No 1512 (92.9%) 1463 (94.1%) 2975(93.5%) Cox Regression Model for Time to First Positively AdjudicatedPrimary Endpoint Including Treatment Group. Delay between randomizationand index MI. Delay between randomization and index MI × Randomizedtreatment group interaction. Age at randomization (years). History ofdiabetes, Prior coronary revascularization (prior PCI or prior CABG) andPrior Heart Failure Interaction Effect p-value Delay betweenrandomization and index 0.2533 MI × Randomized intermittent group Delaybetween randomization and index MI Effect HR (95% CI) p-value  [0-4]days Colchicine vs. placebo 0.58 (0.36; 0.89) 0.0126 [5-20] daysColchicine vs. placebo 0.84 (0.64; 1.11) 0.2120 Notes: Model based on N= 4661 observations. Deaths of undetermined cause were classified as CVdeaths.

TABLE 6 Effect of Colchicine with TTI of <5 days calculated using basicmodel POSITIVELY DELAY BETWEEN ADJUDICATED RANDOMIZATION PRIMARY PlaceboColchicine All AND INDEX MI ENDPOINT N = 2339 N = 2322 N = 4661  [0-5]days N 821 859 1680 Yes 56 (6.8%) 40 (4.7%) 96 (5.7%) No 765 (93.2%) 819(95.3%) 12584 (94.3%) [6-30] days n 1518 1463 2981 Yes 113 (7.4%) 859(5.8%) 198 (6.6%) No 1405 (92.6%) 1378 (94.2%) 2783 (93.4%) CoxRegression Model for Time to First Positively Adjudicated PrimaryEndpoint Including Treatment Group. Delay between randomization andindex MI and Delay between randomization and index MI × Randomizedtreatment group interaction. Interaction Effect p-value Delay betweenrandomization and index 0.5867 MI × Randomized intermittent group Delaybetween randomization and index MI Effect HR (95% CI) p-value  [0-5]days Colchicine vs. placebo 0.67 (0.45; 1.01) 0.0545 [6-30] daysColchicine vs. placebo 0.78 (0.59; 1.03) 0.0764 Notes: Model based on N= 4661 observations. Deaths of undetermined cause were classified as CVdeaths.

TABLE 7 Effect of Colchicine with TTI of <5 days calculated adjustedbasic model POSITIVELY DELAY BETWEEN ADJUDICATED RANDOMIZATION PRIMARYPlacebo Colchicine All AND INDEX MI ENDPOINT N = 2339 N = 2322 N = 4661 [0-5] days N 821 859 1680 Yes 56 (6.8%) 40 (4.7%) 96 (5.7%) No 765(93.2%) 819 (95.3%) 12584 (94.3%) [6-30] days n 1518 1463 2981 Yes 113(7.4%) 859 (5.8%) 198 (6.6%) No 1405 (92.6%) 1378 (94.2%) 2783 (93.4%)Cox Regression Model for Time to First Positively Adjudicated PrimaryEndpoint Including Treatment Group. Delay between randomization andindex MI, Delay between randomization and index MI × Randomizedtreatment group interaction. Age at randomization (years). History ofdiabetes, Prior coronary revascularization (prior PCI or prior CABG) andPrior Heart Failure Interaction Effect p-value Delay betweenrandomization and index 0.5515 MI × Randomized intermittent group Delaybetween randomization and index MI Effect HR (95% CI) p-value  [0-5]days Colchicine vs. placebo 4.43 (0.45, 1.02) 0.0631 [6-30] daysColchicine vs. placebo 0.35 (0.60, 1.05) 0.1023 Notes: Model based on N= 4661 observations. Deaths of undetermined cause were classified as CVdeaths.

For a TTI of 5 days or less, colchicine showed borderline significancewith respect to the benefits of administering colchicine within 5 daysof an MI. This data suggests that some benefit is still possibleadministering colchicine 5 days after an MI, having HR 0.68 (0.45-1.02)and p=0.063 using the adjusted model.

Effects of Time-to-Treatment Initiation on the Secondary and ExploratoryEfficacy Endpoints

The effects of colchicine on the secondary and exploratory endpoints areshown in Table 3. The secondary efficacy endpoint consisting of acomposite of CV death, cardiac arrest, myocardial infarction or strokeoccurred in 3.3% of the patients in the colchicine group and in 6.1% ofthose in the placebo group when TTI was between days 0 and 3 (HR=0.55;95% CI, 0.32-0.95, FIG. 3B). The exploratory endpoint of all coronaryrevascularizations, not coronary revascularizations limited to thoseobserved as the primary composite endpoint, including urgentrevascularization following unstable angina and hospitalization,occurred in 5.5% of patients in the colchicine group, as compared to8.7% of those in the placebo group when TTI was between days 0 and 3(HR=0.63, 95% CI 0.40-0.97). There were 6 deaths in both study groupswhen TTI was between days 0 and 3 (HR=1.03, 95% 0.33-3.19).

This TTI analysis of COLCOT shows that early initiation of low-dosecolchicine within the first 3 days after MI is associated with areduction of 48% in the risk of the primary endpoint consisting of acomposite of CV death, resuscitated cardiac arrest, MI, stroke, orurgent hospitalization for angina requiring coronary revascularization,in comparison with placebo. This result was due to a lower incidence ofMIs, strokes and urgent hospitalizations for angina leading to coronaryrevascularization. The secondary efficacy endpoint consisting of acomposite of CV death, resuscitated cardiac arrest, MI or stroke wasalso significantly reduced by 45% with early initiation of low-dosecolchicine. The benefits were more marked when treatment was initiatedwithin the first 3 days after MI, as compared to between days 4 and 30,supporting the strategy of in-hospital initiation of colchicine in orderto improve CV outcomes post-MI.

The main COLCOT results revealed that colchicine reduced the risk ofischemic CV events by 23% in the post-MI setting. Results from thepresent COLCOT analysis suggest that early suppression of inflammationafter MI provides even greater benefits, with a reduction of 48% in therisk of the composite primary endpoint when colchicine was initiatedbetween days 0 and 3. The demonstrated cost-effectiveness of low-dosecolchicine also supports its large-scale use after MI. Results of theLoDoCo2 study of patients with stable coronary artery disease complementand further support those of COLCOT in the post-MI setting (see Nidorfet al. N Engl Med, 2020. and Tong et al. Circulation, 2020).

Early initiation of low-dose colchicine after MI greatly reduced therisk of ischemic CV events compared with placebo. These results supportin-hospital initiation of adjunctive anti-inflammatory therapy withcolchicine for post-MI prevention.

Statistical Analysis

For the COLCOT trial, it was estimated that a sample of approximately4500 patients undergoing randomization (with 2250 patients in eachgroup) or, in terms of events, a total number of 301 patients with afirst positively adjudicated primary end-point event would yieldadequate power. The sample-size calculation was based on the primaryefficacy end point and assumed a 27% lower risk with colchicine thanwith placebo, indicated by a hazard ratio of 0.724. With the use of atwo-sided test at the 0.05 significance level, the trial would have 80%power if it continued until 301 positively adjudicated primary eventsoccurred in the combined trial groups. The trial design assumed an eventrate of 7% in the placebo group at 24 months, an 18-month recruitmentperiod during which patients would be uniformly recruited, a 24-monthminimum follow-up period, and a 1% annual rate of loss to follow-up orwithdrawal of consent.

The efficacy analyses were conducted with the use of positivelyadjudicated data and according to the intention-to-treat principle. Theprimary end point was compared between the two trial groups with the useof a log-rank test, and the hazard ratio from a Cox proportional-hazardsmodel, with a 95% confidence interval, was calculated. A Coxproportional-hazards model with adjustment for important baselinecharacteristics was also used as prespecified in the protocol.

For the present TTI analysis, the data were centrally analyzed by anindependent academic biostatistics center at the Montreal HealthInnovations Coordinating Center. The analysis was conducted amongstpatients who received at least one dose of the study medication(referred to as the safety population in the main protocol, FIG. 1 ).TTI was defined as the length of time in days between the index MI andthe initiation of the study medication, and three specific cutoffs wereanalyzed day 3, days 4 to 7, and day 8). Early initiation of therapy wasdefined as TTI 3 days. Baseline characteristics were summarized usingcounts and percentages for categorical variables and mean±standarddeviation (SD) for continuous variables. For each baselinecharacteristic, comparisons were made using ANOVA for continuousvariables and Chi-Square test for categorical variables according to TTIstrata. Analyses of the efficacy endpoints, expressed as time to event,were conducted according to time to treatment initiation. Adjustedhazard ratios (HR) along with 95% confidence intervals (CI) werecalculated from stepwise multivariable Cox regression models adjustedfor the same covariates that were used in the main analysis of theCOLCOT trial (FIG. 2 ). All statistical tests were two-sided andconducted at the 0.05 significance level. Statistical analyses wereperformed with the use of SAS software, version 9.4 (SAS Institute).

EXAMPLES

The following examples are provided to further illustrate someembodiments of the present invention, but are not intended to limit thescope of the invention; it will be understood by their exemplary naturethat other procedures, methodologies, or techniques known to thoseskilled in the art may alternatively be used.

Example 1: Meta-Analysis of Randomized Controlled Trials (RCTs) ofColchicine for Secondary Prevention of Cardiovascular Disease

Data sources Medline (PUBMED), EMBASE, and Cochrane central weresearched to identify RCTs comparing colchicine to placebo or nocolchicine for secondary cardiovascular prevention (inception to Sep. 1,2020). To maximized sensitivity, citation chasing was performed inGoogle Scholar, Scopus, and Web of Science. Secondary prevention wasdefined as patients with clinically manifest or established CAD. Queryterms included “colchicine”, “coronary artery disease”, “acute coronarysyndrome”, “myocardial infarction”, “cardiovascular disease”,“atherosclerosis”, and “secondary prevention”, either separately or incombination.

Study Selection, Data Extraction, and Bias Assessment

RCTs that met the following criteria were included in themeta-analysis: 1) compared daily use of low-dose (0.5 mg) colchicine toplacebo or no colchicine for secondary cardiovascular prevention; 2) thestudy reported at least one of the following outcomes: cardiovasculardeath, MI, stroke, cardiac arrest, or urgent coronary revascularization;3) other than the trial medication, patients in both arms were treatedin accordance to guideline directed medical therapy; 4) the minimumfollow-up was at least 1 year; and 5) trials were published in apeer-reviewed scientific journal. Review articles, editorials,meta-analyses, observational studies, and published abstracts wereexcluded from the present meta-analysis.

Study selection was performed by two independent reviewers, using twolevels of screening. At the first level, titles and abstracts ofsearched studies were screened, followed by review of full texts. Thereviewers were not blinded to the title of the journals, authors, oraffiliated institutions. Reasons for exclusion were recorded and anydiscrepancies were discussed until a consensus was achieved.

Using standardized forms, data on study characteristics, patientcharacteristics, and outcomes were extracted on the intent-to-treatpopulation independently by two reviewers from each eligible study. TheCochrane Collaboration risk-of-bias tool for randomized trials was usedto evaluate study quality. The meta-analysis was conducted in accordanceto the Preferred Reporting Items for Systematic Reviews andMeta-Analyses (PRISMA) guidelines.

Outcomes

The primary efficacy endpoint was a composite of cardiovascular death,MI, ischemic stroke, and urgent coronary revascularization. Secondaryefficacy endpoints consisted of the components of the primary endpoint,composite of cardiovascular death, MI, and ischemic stroke, as well asdeep vein thrombosis or pulmonary embolus, and atrial fibrillation (AF).To maximize consistency in pooling efficacy endpoints among trials, theprimary and secondary composite efficacy and stroke endpoints in COLCOTwere modified to meet the definition of primary and stroke endpoints ofthe LoDoCo2 trial. Therefore, adjudicated events of resuscitated cardiacarrest and non-ischemic stroke in COLCOT were excluded from the pooledprimary endpoint. The component endpoint of stroke was also restrictedto include only ischemic strokes. Incidence rates and hazards ratios(HRs) were calculated for the new primary composite endpoint andischemic stroke endpoint using individual patient data from COLCOT.

Safety outcomes were limited to serious adverse events (SAEs) andincluded all-cause and non-cardiovascular mortality, hospitalization forgastrointestinal event, infection, and pneumonia, as well as diagnosisof cancer. Incidence of SAEs were recalculated for COLCOT using theintent-to-treat population.

Data Synthesis and Statistical Analyses

The DerSimonian and Laird random-effects model was used to calculate thepooled HR and corresponding 95% confidence intervals (CI) for primaryand secondary endpoints in the overall trial and in subgroup analyses ofthe primary endpoint. For safety outcomes, the DerSimonian and Lairdrandom-effects model was used to compute risk ratios (RR) andcorresponding 95% CIs. Heterogeneity was evaluated with the Higgins 12statistic. 12 values of <25%, 25-75%, and >75% were considered toindicate low, moderate, and high degrees of heterogeneity, respectively.In subgroup analyses, the Ob statistic was calculated to determineinconsistency and variability in the treatment effect between strata.Publication and small study bias were assessed with the Egger'sregression test and visually by asymmetry in funnel plots. Sensitivityanalyses were performed for the primary composite and component outcomesfor 1) RCTs in patients with acute coronary syndrome (COLCOT and COPS),and 2) RCTs in patients with stable CAD (LoDoCo and LoDoCo2); and afterexclusion of 3) the LoDoCo trial [open-label trial and control group wasnot randomized to placebo] and 4) the LoDoCo and COPS [increased dose(0.5 mg twice daily) of colchicine prescribed during first month]trials. Statistical analyses were performed using SAS software version9.4 (SAS Institute, Cary, North Carolina) and Stata (Version 16,StataCorp, College Station, Texas).

Results Literature Search Results and Risk of Bias

The search strategy identified 79 studies. After the first- andsecond-level screening processes, four RCTs were retained in the presentmeta-analysis. The characteristics of included RCTs are listed in Table8. The Low-Dose Colchicine (LoDoCo) and Low-Dose Colchicine 2 (LoDoCo2)trials assessed the efficacy of colchicine in patients with stable CAD(defined as clinically stable for ≥6 months) (see, Nidorf et al. N EnglMed, 2020. and Tong et al. Circulation, 2020). In comparison, theColchicine Cardiovascular Outcomes Trial (COLCOT) was conducted inpatients who had a recent MI (≤30 days) and the Colchicine in Patientswith acute coronary Syndrome (COPS) trial enrolled patients with acutecoronary syndromes (ACS) (see, Tardif et al. N Engl J Med.)

The pooled sample size of enrolled patients was 11,594, of which 5774patients were randomized to colchicine and 5820 patients were randomizedto placebo (or no colchicine, in the LoDoCo trial only). Three trialswere designated as “low risk” for overall bias (see, Tardif et al. NEngl J Med., Nidorf et al., N Engl J Med, 2020, and Tong et al,Circulation, 2020) and 1 trial was marked as being of “some concern”(see, Nirdorf et al., J Am Coll Cardiol. 2013; 61: 404-10) in theCochrane Collaboration risk-of-bias assessment.

TABLE 8 Study characteristics LoDoCo COLCOT COPS LoDoCo2 Year 2013 20192020 2020 Study design Single-blind RCT Double-blind, Double-blind,placebo Double-blind, placebo controlled controlled RCT placebocontrolled RCT RCT Study Stable CAD Recent MI (<30 ACS Stable CADpopulation days) N 532 4,745 795 5,522 Key inclusion Angiographically MIwithin 30 days ACS Evidence of CAD criteria proven CAD; prior; completed(STEMI/NSTEMI/UA); on invasive clinically stable planned Evidenced CADon angiography or for <=6 months percutaneous coronary angiography,computed revascularization managed with either tomography procedures;PCI or medical angiography or a treated according therapy coronarycalcium to national score of ≥400 guidelines that Agaston units on aincluded intensive coronary-artery use of statins calcium scan;clinically stable condition for ≥6 months Key Bypass surgery Severeheart CAD requiring surgical Moderate-to- exclusion within 10 yearsfailure; left revascularization pre- severe renal criteria priorventricular ejection existing long-term impairment; fraction <35%;colchicine use or severe stroke within the immunosuppressant heartfailure; previous 3 therapy; severe severe valvular months; type 2hepatic or renal disease index MI; insufficiency; known coronary-bypassactive malignancy surgery either within previous 3 years or planned;severe renal or hepatic disease; known cancer Median 24 months 22.6months 12 months 28.6 months follow-up Primary Composite: ACS,Composite: CV Composite: All-cause Composite: CV endpointout-of-hospital mortality, mortality, ACS death, MI, cardiac arrest, orresuscitated (STEMI/NSTEMI/UA), ischemic stroke, or non-cardioemboliccardiac arrest, MI, ischemia-driven ischemia-driven ischemic strokestroke, or urgent revascularization, or coronary hospitalization fornon-cardioembolic revascularization angina requiring ischemic strokerevascularization *ACS, acute coronary syndrome; CAD, coronary arterydisease; CV, cardiovascular; MI, myocardial infarction; RCT, randomizedcontrolled trial; STEM, ST elevation myocardial infarction; NSTEMI,non-ST elevation myocardial infarction; UA, unstable angina

Patient Characteristics

Baseline patient characteristics for each RCT are summarized in Table 9.The mean age of patients ranged from 60 to 67 years. In all trials, <20%of enrolled patients were women and more than 90% of patients were onconcomitant statin therapy. LoDoCo and LoDoCo2 trials had a higherproportion of patients who underwent prior coronary revascularization[percutaneous coronary intervention (PCI) and coronary artery bypassgraft (CABG) surgery]. The distribution of all other patientcharacteristics was relatively similar between trials.

TABLE 9 Patient characteristics at baseline LoDoCo COLCOT COPS LoDoCo2Colchicine Control Colchicine Placebo Colchicine Placebo ColchicinePlacebo N = 250 N = 282 N = 2366 N = 2379 N = 396 N = 399 N = 2762 N =2760 Age, years 67 ± 9.2 66 ± 9.6 60.6 ± 10.7 60.5 ± 10.6 59.7 ± 10.260.0 ± 10.4 65.8 ± 8.4 65.9 ± 8.7 (mean ± SD) Women (%) 11.2% 11.0%19.9% 18.4% 18.7% 22.3% 16.5% 14.1% Hypertension (%) Not reported Notreported 50.1% 52.0% 50.8% 49.9% 51.4% 50.3% Diabetes (%) 27.6% 32.6%19.5% 20.9% 18.9% 19.0% 17.8% 18.7% History of PCI (%) 55.2% 59.9% 16.6%17.1% 12.9% 12.5% 76.0% 75.3% History of CABG (%) 15.6% 22.0% 2.9% 3.4%3.8% 4.8% 11.5% 14.2% Statin use (%) 94.0%* 96.1%* 98.9% 99.1% 98.2%99.5% 93.9% 94.0% *The LoDoCo trial only reported use of high dosestatins, not any statin use.

Clinical Efficacy Endpoints

Clinical efficacy results from each trial are presented in Table 10. Inpatients with CAD, the addition of colchicine to standard medicaltherapy was associated with a statistically significant reduction in theprimary composite endpoint of cardiovascular mortality, MI, ischemicstroke, and urgent coronary revascularization, compared to patients onplacebo or no colchicine [pooled HR 0.68 (95% CI 0.54-0.81); I²=37.7%].The reduction in cardiovascular events in patients randomized tocolchicine was driven by statistically significant reductions in theincidence of MIs [pooled HR 0.62 (95% CI 0.36-0.88); I²=68.76%],ischemic strokes [pooled HR 0.38 (95% CI 0.13-0.63); I²=0.0%], andurgent coronary revascularization [pooled HR 0.56 (95% CI 0.30-0.82);I²=65.1%]. However, there was no statistically significant differencedetected for cardiovascular mortality. Sensitivity analyses that pooledthe results of COLCOT and LoDoCo2 trials demonstrated similar effectestimates for the primary composite and component outcomes, althoughmagnitude of effect and heterogeneity (12) between studies decreased.

TABLE 10 Study efficacy outcomes LoDoCo¹¹ COLCOT¹⁰ COPS¹³ LoDoCo2¹²Colchicine Control Colchicine Placebo Colchicine Placebo ColchicinePlacebo N = 250 N = 282 N = 2366 N = 2379 N = 396 N = 399 N = 2762 N =2760 Primary composite outcome: Cardiovascular mortality, myocardialinfarction, ischemic stroke, urgent revascularization Events, NA NA 130168 19 41 187 264 N (%) (5.5%) (7.1%) (4.8%) (10.3%) (6.8%) (9.6%) HR NA0.77 (0.61-0.97) 0.47 (0.27-0.82) 0.69 (0.57-0.83) (95% CI)Cardiovascular mortality Events, NA NA 20 24 3 1 20 25 N (%) (0.8%)(1.0%) (0.8%) (0.3%) (0.7%) (0.9%) HR NA 0.84 (0.46-1.52)  3.09(0.32-29.71) 0.80 (0.44-1.44) (95% CI) Myocardial infarction Events, 414 89 98 11 22 83 116 N (%) (1.6%) (5.6%) (3.8%) (4.1%) (3.7%) (5.5%)(3.0%) (4.2%) HR 0.25 (0.08-0.76) 0.91 (0.68-1.21) 0.52 (0.25-1.07) 0.70(0.53-0.93) (95% CI) Ischemic stroke Events, 1 4 4 16 2 6 16 24 N (%)(0.4%) (1.6%) (0.2%) (0.7%) (0.5%) (1.5%) (0.6%) (0.9%) HR 0.23(0.03-2.03) 0.25 (0.08-0.75) 0.34 (0.07-1.70) 0.66 (0.35-1.25) (95% CI)Urgent coronary revascularization Events, NA NA 25 50 3 12 135 177 N (%)(1.1%) (2.1%) (0.8%) (3.0%) (4.9%) (6.4%) HR NA 0.50 (0.31-0.81) 0.26(0.07-0.92) 0.75 (0.60-0.94) (95% CI) *NA = not applicable. A studyresult was designed NA when the outcome in the study did not closelymatch the outcome in the present meta-analysis.

In sensitivity analyses of ACS trials (COLCOT and COPS; N=5540), theprimary composite endpoint, MI, and urgent coronary revascularizationswere statistically significantly reduced in patients randomized tocolchicine compared to placebo. Among patients with stable CAD (LoDoCoand LoDoCo 2; N=6054), the only comparable outcome between trials was MIwhich was statistically significantly decreased with colchicine comparedto placebo.

Although there was no statistically significant difference in theincidence of key secondary endpoints, there was a trend towards reducedAF diagnoses and AF episodes among patients randomized to colchicine[pooled HR 0.86 (95% CI 0.67-1.04); 12=0.0%].

Visual inspection of funnel plots and the results of the Eggers testindicated there was no significant risk of publication bias for alloutcomes (p>0.05 for all) except urgent coronary revascularization(p=0.02).

Subgroup Analyses

The statistically significant reduction in the incidence of the primarycomposite cardiovascular endpoint among patients randomized tocolchicine was consistent for most subgroup analyses. There was nosignificant heterogeneity of the effect of colchicine in the differentsubgroups studied. Overall, the Ob statistic suggests that there isminimal variability and inconsistency in the treatment effect betweenstrata in subgroup analyses (p>0.05 for all).

Major Adverse Events

There was no statistically significant difference between treatment armsfor the risk of all-cause [pooled RR 1.04 (95% CI 0.61-1.78); I²=62.01%]and non-cardiovascular mortality [pooled RR 1.38 (95% CI 0.99-1.93);I²=0.0%] (FIG. 3 ). The rates of infections, pneumonias,hospitalizations for gastrointestinal events, and diagnoses of cancerwere also not significantly different. For pneumonia, there was a highdegree of heterogeneity between trials with opposite directions for thetreatment effect (I²=81.5%).

In this contemporary meta-analysis of RCTs comparing colchicine toplacebo (or no colchicine) for secondary cardiovascular prevention, wefound that: 1) treatment with colchicine was associated with a 32%reduction in the incidence of major cardiovascular events; 2)significantly fewer MIs, ischemic strokes, and urgent coronaryrevascularizations were the primary drivers for the overall decrease incardiovascular events; 3) the protective treatment effect of colchicinewas relatively consistent among most subgroups studied, and 4)colchicine had a favorable safety profile. This is the firstcomprehensive meta-analysis of RCTs evaluating efficacy and safety ofcolchicine for secondary cardiovascular prevention in which theendpoints were harmonized across trials. Overall, the synthesis ofcurrent evidence in the present meta-analysis indicates that treatmentwith colchicine for secondary cardiovascular prevention confersbeneficial clinical effects.

Secondary Prevention of Cardiovascular Diseases

Although the 4 RCTs investigated the efficacy of colchicine in differentsegments of the CAD population, including stable CAD, recent MI, andACS, the results of all trials consistently demonstrated that colchicinewas protective against a composite endpoint of cardiovascular mortality,MI, ischemic stroke, and urgent coronary revascularization. Theindividual trials were not powered to detect statistically significantdifferences in the components of the primary endpoint. Whereas alltrials showed a decrease in urgent coronary revascularizations amongpatients randomized to colchicine, only COLCOT detected a reduction inischemic strokes [HR 0.25 (95% CI 0.08-0.75)] and LoDoCo2 a decrease inMIs [HR 0.70 (95% CI 0.53-0.93)]. Pooling HRs from the RCTs revealedthat the attenuated risk of major cardiovascular events was attributedto risk reductions of 38%, 62%, and 44% for MIs, ischemic strokes, andurgent coronary revascularization, respectively. Although the 2 largesttrials, COLCOT and LoDoCo2, contributed the most weight to analyses, theinclusion of LoDoCo and COPS tended to increase the magnitude of therisk reduction by 4-5%.

Individual trials and pooled results suggest that there is no differencein the incidence of cardiovascular or all-cause mortality withcolchicine. These pooled analyses provide reassurance about the safetyof colchicine for the outcome of all-cause mortality. Results from boththe LoDoCo2 and COPs trials showed a trend towards increased all-causemortality with colchicine, although neither reached statisticalsignificance [LoDoCo2 HR 1.21 (95% CI 0.86-1.71) and COPS HR 8.20 (95%1.02-65.61)]. The increased power from pooled analyses demonstrated thatthe effect of colchicine on all-cause mortality was closer to null or noeffect than suggested by individual trials [pooled RR 1.04 (95% CI0.61-1.78)]. The anti-inflammatory properties of colchicine work throughvarious mechanisms to inhibit the pathogenesis of CAD, and subsequentlyreduce the incidence of ischemic cardiovascular events. In addition totargeting the NLRP3 inflammasome leading to the reduction of circulatinglevels of IL-1β and IL-6, colchicine also inhibits cholesterol crystalsthat promote inflammation and plaque instability in atherosclerosis.

Treatment Effects Across Subgroups

The treatment effect of colchicine was similar with overlappingconfidence intervals across age categories (≤65 or >65 years), presenceor absence of diabetes and hypertension, and among patients with orwithout prior coronary revascularization. Although the risk reductionappeared less marked in women compared to men, less than 20% of trialpopulations were women (1977 women compared to 9617 men). It is,therefore, possible that the lack of a statistically significantreduction in cardiovascular events with colchicine in the subgroupanalysis of women reflects limited power. There was no significantheterogeneity between the effects in subgroups and that in the overallpopulation.

Safety

Colchicine has an established safety profile from its centuries of useto treat gout. There was a numerical imbalance in the number ofnon-cardiovascular deaths between study arms, which did not reachstatistical significance. Importantly, there was no effect of colchicineon all-cause mortality. In the COPS study, the increased dose ofcolchicine during the first month of follow-up might have contributed tohigher non-cardiovascular deaths. In addition, 3 of 5 colchicinepatients who died from non-cardiovascular causes in COPS had alsodiscontinued colchicine prior to date of death, which may suggest thaton-treatment analyses may provide further evidence to the safety ofcolchicine for non-cardiovascular mortality. Furthermore, the quality offollow-up in COPS was poor, with more than twice the number of patientswith incomplete vital status than that of deaths due to inadequateresources (2 part-time healthcare workers following 795 patients). Incontrast, the quality of follow-up and rate of vital statusascertainment of the 10,267 patients included in COLCOT and LoDoCo2 wereexcellent and did not reveal a significant difference innon-cardiovascular mortality between study arms. Finally, themeta-analysis showed no difference in all-cause mortality betweengroups.

Only the COLCOT trial detected a difference in the rate of pneumoniabetween patients randomized to colchicine (0.9%) or placebo (0.4%).Pooled analyses of COLCOT and LoDoCo2 did not show an increased risk ofpneumonia with colchicine, suggesting this result in the former may havebeen due to chance. The lack of a difference between groups forinfections, hospitalizations, and diagnoses of cancer further validatesthat colchicine is safe to use in patients with CAD.

As we did not have access to patient-level data from 3 of 4 trials, onlymodified study-level data was used for the present meta-analysis.Although meta-analyses based on aggregate patient data continue to bethe mainstay of systematic reviews that inform clinical practice,meta-analyses based on individual patient data have several advantagesincluding the ability to verify data, address new questions, and adjustfor the same variables across studies. Finally, the small number ofeligible studies precluded meta-regression analyses to determine theinfluence of specific variables or effect modifiers on the associationbetween colchicine and cardiovascular events. Nevertheless, thepotential for effect modification was addressed in part by subgroupanalyses.

In patients with CAD, the addition of low-dose colchicine to standardmedical therapy consistently and significantly reduces the incidence ofmajor cardiovascular events compared to standard medical therapy alone.With the exception of cardiovascular mortality, significant reductionswere observed for components of the primary outcome, including MIs,ischemic strokes, and urgent coronary revascularizations.

Example 2: Administration of Low-Dose Colchicine after MyocardialInfarction

The results of the main COLCOT trial support that the use of colchicinein patients who have had a myocardial infarction in the past 30 dayssignificantly improved their quality of life in several ways. The COLCOTtrial was performed as follows. A randomized, double-blind trialinvolving patients recruited within 30 days after a myocardialinfarction was performed. The patients were randomly assigned to receiveeither low-dose colchicine (0.5 mg once daily) or placebo. A total of4745 patients were enrolled; 2366 patients were assigned to thecolchicine group, and 2379 to the placebo group. Patients were followedfor a median of 22.6 months to observe the occurrence of the primaryefficacy end point which was a composite of death from cardiovascularcauses, resuscitated cardiac arrest, myocardial infarction, stroke, orurgent hospitalization for angina leading to coronary revascularization.The components of the primary end point and safety were also assessed inthis study.

In this randomized, double-blind, placebo-controlled,investigator-initiated trial, we assigned patients in a 1:1 ratio toreceive either colchicine (at a dose of 0.5 mg once daily) or placebo.The trial protocol, available at NEJM.org, was designed by a trialsteering committee.

Trial Population

Adult patients were eligible if they had had a myocardial infarctionwithin 30 days before enrollment, had completed any planned percutaneousrevascularization procedures, and were treated according to nationalguidelines that included the intensive use of statins.

Patients were excluded if they had severe heart failure, a leftventricular ejection fraction of less than 35%, stroke within theprevious 3 months, a type 2 index myocardial infarction, coronary-bypasssurgery either within the previous 3 years or planned, a history ofnoncutaneous cancer within the previous 3 years, inflammatory boweldisease or chronic diarrhea, neuromuscular disease or a nontransientcreatine kinase level that was greater than three times the upper limitof the normal range (unless due to infarction), clinically significantnontransient hematologic abnormalities, severe renal disease with aserum creatinine level that was greater than two times the upper limitof the normal range; severe hepatic disease, drug or alcohol abuse,current or planned long-term systemic glucocorticoid therapy, or ahistory of clinically significant sensitivity to colchicine.

Written informed consent was obtained from all the patients beforeenrollment. Clinical evaluations occurred at 1 month and 3 months afterrandomization and every 3 months thereafter.

End Points

The primary efficacy end point was a composite of death fromcardiovascular causes, resuscitated cardiac arrest, myocardialinfarction, stroke, or urgent hospitalization for angina leading tocoronary revascularization in a time-to-event analysis.

The secondary end points consisted of the components of the primaryefficacy end point; a composite of death from cardiovascular causes,resuscitated cardiac arrest, myocardial infarction, or stroke; and totalmortality in time-to-event analyses. Coronary revascularization,hospitalization for heart failure, atrial fibrillation, and deep venousthrombosis or pulmonary embolus were prespecified as exploratory endpoints in the protocol.

Additional prespecified exploratory end points included the change frombaseline to 6 months in the high-sensitivity C-reactive protein leveland the change from baseline to 12 months in the white-cell count. TheC-reactive protein biomarker substudy was implemented after a protocolamendment and was optional for sites and for patients; 34 sites chose toparticipate in this substudy.

All serious adverse events were recorded. The only other adverse eventsrecorded were those that were considered to be related to thegastrointestinal system, events that were judged by the investigator tobe related to colchicine or placebo, or laboratory abnormalities thathad been judged by the investigator to be clinically significant,

Statistical Analysis

In this event-driven trial, it was estimated that a sample ofapproximately 4500 patients undergoing randomization (with 2250 patientsin each group) or, in terms of events, a total number of 301 patientswith a first positively adjudicated primary end-point event would yieldadequate power. The sample-size calculation was based on the primaryefficacy end point and assumed a 27% lower risk with colchicine thanwith placebo, indicated by a hazard ratio of 0.724. With the use of atwo-sided test at the 0.05 significance level, the trial would have 80%power if it continued until 301 positively adjudicated primary eventsoccurred in the combined trial groups. The trial design assumed an eventrate of 7% in the placebo group at 24 months, an 18-month recruitmentperiod during which patients would be uniformly recruited, a 24-monthminimum follow-up period, and a 1% annual rate of loss to follow-up orwithdrawal of consent.

The efficacy analyses were conducted with the use of positivelyadjudicated data and according to the intention-to-treat principle. Theprimary end point was compared between the two trial groups with the useof a log-rank test, and the hazard ratio from a Cox proportional-hazardsmodel, with a 95% confidence interval, was calculated. A Coxproportional-hazards model with adjustment for important baselinecharacteristics was also used as prespecified in the protocol.

The analysis of the primary end point was repeated in the per-protocolpopulation (i.e., patients without major protocol deviations). Secondaryand exploratory end points expressed as time to event were analyzedsimilarly. The changes from baseline to follow-up were analyzed with theuse of an analysis of covariance model with adjustment for baselinevalue, and estimates of treatment effect are presented with 95%confidence intervals.

The efficacy end points expressed as time to event could be assessed inall patients because the event dates and censoring dates were complete,with the exception of one incomplete event date for atrial fibrillation;therefore, imputation for missing data was not done.

In the analysis of time to event, the following censoring rules wereused. For death from any cause and death from cardiovascular causes,data from event-free patients who completed the trial were censored atthe date of trial completion, and data from patients who did notcomplete the trial, such as those who were lost to follow-up or whowithdrew consent, were censored at the date of last contact or the dateof the assessment of survival status, whichever was later.

For the analysis of death from cardiovascular causes, patients who diedfrom a noncardiovascular cause had their data censored at the time ofdeath.

For all other end points, including the primary end point, the samecensoring rules applied, but the survival status was not used because noformal assessment of end points was done at the assessment of survivalstatus.

An analysis of the components of the primary end point with death fromnoncardiovascular causes as a competing event for death fromcardiovascular causes, and with death from any cause as a competingevent for the other components, was conducted with the use of the Fineand Gray subdistribution hazard model (Fine J P and Gray R J, Aproportional hazards model for the subdistribution of a competing risk.J Am Stat Assoc 1999; 94:496-509). No missing data were imputed exceptfor age

To account for the occurrence of multiple primary end-point eventswithin patients, recurrent-event analyses were undertaken with the useof negative binomial regression, Andersen-Gill, and Wei-Lin-Weissfeldmodels (Rogers J K et al., Analysing recurrent hospitalizations in heartfailure: a review of statistical methodology, with application toCHARM-Preserved. Eur J Heart Fai/2014; 16:33-40; Andersen P K and Gill RD, Cox's regression model for counting processes: a large sample study.Ann Stat 1982; 10:1100-20; Lin D Y and Wei L J, The robust inference forthe proportional hazards model. J Am Stat Assoc 1989; 84:1074-8; Lin D Yet al. Semiparametric regression for the mean and rate functions ofrecurrent events. J R Stat Soc 2000; 62:711-30; Wei L J and Glidden D V,An overview of statistical methods for multiple failure time data inclinical trials. Stat Med 1997; 16:833-9; Ghosh D, Methods for analysisof multiple events in the presence of death. Control Clin Trials 2000;21:115-26; Li Q H and Lagakos S W, Use of the Wei-Lin-Weissfeld methodfor the analysis of a recurring and a terminating event. Stat Med 1997;16:925-40; Metcalfe C and Thompson S G, The importance of varying theevent generation process in simulation studies of statistical methodsfor recurrent events. Stat Med 2006; 25:165-79; Jahn-Eimermacher A,Comparison of the Andersen-Gill model with Poisson and negative binomialregression on recurrent event data. Comput Stat Data Anal 2008;52:4989-97).

An interim analysis was performed after 50% of the primary end-pointevents had been positively adjudicated. The prespecified stopping rulefor efficacy was based on the Lan-DeMets procedure with theO'Brien-Fleming alpha-spending function. After review of the interimresults, the data and safety monitoring board recommended that the trialshould continue as planned.

To account for this interim analysis, the statistical significance levelwas set to 0.0490 for the final analysis of the primary end point. Allother statistical tests were two-sided and conducted at the 0.05significance level. Statistical analyses were performed with the use ofSAS software, version 9.4 (SAS Institute). There was no prespecifiedplan to adjust for multiple comparisons across the multiple methods thatwere used to analyze the primary and secondary end points; results ofthese analyses are reported with point estimates and 95% confidenceintervals, without P values. The 95% confidence intervals were notadjusted for multiple comparisons, and inferences drawn from them maynot be reproducible. The final amendment to the statistical analysisplan was approved on Aug. 28, 2019, before unblinding of the trial-groupassignments occurred.

Results Patients

Trial enrollment began in December 2015 and was completed in August2018; the last trial visit was in July 2019. A total of 4745 patientsunderwent randomization (with 2366 being assigned to the colchicinegroup and 2379 to the placebo group) and were followed for a median of22.6 months. At the time of the database lock on Aug. 28, 2019, andunblinding on Aug. 29, 2019, vital status was available for all except23 patients (99.5%); 89 patients (1.9%) were lost to follow-up, and 30patients (0.6%) withdrew consent.

The characteristics of the patients at baseline are shown in Table 10.

TABLE 10 Characteristics of the Patients Colchicine PlaceboCharacteristic (N = 2366) (N = 2379) Age - yr 60.6 ± 10.7  60.5 ± 10.6Female sex - no. (%) 472 (19.9) 437 (18.4) White race - no./total no.(%)† 1350/1850 (73.0) 1329/1844 (72.1) Body-mass index 28.2 ± 4.8  28.4± 4.7 Current smoking - no./total no. (%) 708/2366 (29.9) 708/2377(29.8) Hypertension - no. (%) 1185 (50.1) 1236 (52.0) Diabetes - no. (%)462 (19.5) 497 (20.9) History of myocardial infarction - no. (%) 370(15.6) 397 (16.7) History of PCI - no. (%) 392 (16.6) 406 (17.1) Historyof CABG - no. (%) 69 (2.9) 81 (3.4) History of heart failure - no. (%)48 (2.0) 42 (1.8) History of stroke or TIA - no. (%) 55 (2.3) 67 (2.8)Time from index myocardial infarction to 13.4 ± 10.2 13.5 ± 10.1randomization - days PCI for index myocardial infarction - no./total no.2192/2364 (92.7) 2216/2375 (93.3) (%) Medication use - no. (%) Aspirin2334 (98.6) 2352 (98.9) Other antiplatelet agent 2310 (97.6) 2337 (98.2)Statin 2339 (98.9) 2357 (99.1) Beta-blocker 2116 (89.4) 2101 (88.3) *Plus-minus values are means ± SD. Data were missing on the followingcharacteristics: age (assessed according to date of birth; see below),for 435 patients; body-mass index (the weight in kilograms divided bythe square of the height in meters), for 5; and information about theindex myocardial infarction, for 6. Date of birth and race were notrequired fields because both were considered in some countries to besensitive data that could allow for the identification of patients. Forstatistical reporting, missing information regarding the day of birthwas replaced by 15, and missing information regarding the month and dayof birth was replaced by July 1. CABG denotes coronary-artery bypassgraft surgery, PCI percutaneous coronary intervention, and TIA transientischemic attack. †Race was reported by the patient.

Patients were enrolled a mean of 13.5 days after myocardial infarction.The mean age of the patients was 60.6 years, 19.2% of the patients werewomen, and 20.2% had diabetes. Most patients (93.0%) underwentpercutaneous coronary intervention for their index myocardialinfarction. Aspirin, a different antiplatelet agent, and a statin weretaken by 98.8%, 97.9% and 99.0% of the patients, respectively.

At the end of the trial, the trial regimen had been discontinued in18.4% of the patients in the colchicine group and in 18.7% of those inthe placebo group. Among the patients who discontinued the trialregimen, the median time of taking the trial drug was 7.1 months(interquartile range, 1.9 to 14.6) in the colchicine group, as comparedwith 6.1 months (interquartile range, 1.6 to 14.4) in the placebo group.Overall, the median duration of receipt of the trial drug was 19.6months in the colchicine group and 19.5 months in the placebo group.

Clinical Efficacy End Points

A primary end-point event occurred in 5.5% of the patients in thecolchicine group, as compared with 7.1% of those in the placebo group(hazard ratio, 0.77; 95% confidence interval [CI], 0.61 to 0.96; P=0.02by the log-rank test). A multivariable Cox regression model withadjustment for baseline covariates yielded a similar result (Table 11).

TABLE 11 Multivariable Cox Regression Model for Time to First PrimaryEndpoint. Adjusted Hazard Effect Ratio (95% CI) P Value Randomizedtreat- Colchicine vs. 0.78 (0.62-0.98) 0.03 ment group Placebo Age atrandomization 1.02 (1.01-1.03) <0.001 (years) History of diabetes Yesvs. No 1.86 (1.46-2.37) <0.001 Prior coronary Yes vs. No 2.02(1.58-2.58) <0.001 revascularization (PCI or CABG) Prior heart failureYes vs. No 1.81 (1.08-3.04) 0.03

CABG denotes coronary artery bypass graft, and PCI percutaneous coronaryintervention. The model was based on 4745 observations. All baselinecharacteristics that showed an association (P<0.20) with the occurrenceof a first positively adjudicated primary endpoint were included in thestepwise multivariable Cox regression. For age at randomization, thehazard ratio is for an increase of one year of age.

In the prespecified per-protocol analysis involving patients who adheredto the protocol, the primary end point occurred in 5.1% of the patientsin the colchicine group and in 7.1% of those in the placebo group(hazard ratio, 0.71; 95% CI, 0.56 to 0.90) (Table 12).

TABLE 12 Rates and Hazard Ratios for the Primary Endpoint and itsComponents in the Per-Protocol Population†. Clinical Outcome HazardPer-protocol Colchicine Placebo Ratio population N = 2260 N = 2270 (95%CI) Primary 115 (5.1%) 162 (7.1%) 0.71 (0.56-0.90) endpoint - no. (%) CVdeath - no. (%) 19 (0.8%) 23 (1.0%) 0.83 (0.45-1.53) Resuscitated 5(0.2%) 5 (0.2%) 1.00 (0.29-3.46) cardiac arrest - no. (%) MI - no. (%)77 (3.4%) 92 (4.1%) 0.84 (0.62-1.14) Stroke - no. (%) 5 (0.2%) 19 (0.8%)0.26 (0.10-0.71) Urgent 22 (1.0%) 47 (2.1%) 0.47 (0.28-0.78)hospitalization for angina requiring revascularization - no. (%) CVdenotes cardiovascular, and MI myocardial infarction. †The per-protocolpopulation consisted of patients without major protocol deviations.

Table 13 shows the percentages of patients with events and the hazardratios for the components of the primary end point, including death fromcardiovascular causes (hazard ratio, 0.84; 95% CI, 0.46 to 1.52),resuscitated cardiac arrest (hazard ratio, 0.83; 95% CI, 0.25 to 2.73),myocardial infarction (hazard ratio, 0.91; 95% CI, 0.68 to 1.21), stroke(hazard ratio, 0.26; 95% CI, 0.10 to 0.70), and urgent hospitalizationfor angina leading to coronary revascularization (hazard ratio, 0.50;95% CI, 0.31 to 0.81). The hazard ratios remained unchanged in theanalysis that took competing events into account.

TABLE 13 Major Clinical End-points (Intention-to-Treat Population)Colchicine Placebo (N = 2366) (N = 2379) Hazard Ratio End Point number(percent) (95% CI) P Value Primary composite end point 131 (5.5) 170(7.1) 0.77 (0.61-0.96) 0.02† Components of primary end point Death fromcardiovascular causes 20 (0.8) 24 (1.0) 0.84 (0.46-1.52) Resuscitatedcardiac arrest 5 (0.2) 6 (0.3) 0.83 (0.25-2.73) Myocardial infarction 89(3.8) 98 (4.1) 0.91 (0.68-1.21) Stroke 5 (0.2) 19 (0.8) 0.26 (0.10-0.70)Urgent hospitalization for angina 25 (1.1) 50 (2.1) 0.50 (0.31.-0.81)leading to revascularization Secondary composite end point† 111 (4.7)130 (5.5) 0.85 (0.66-1.10) Death 43 (1.8) 44 (1.8) 0.98 (0.64-1.49) Deepvenous thrombosis 10 (0.4) 7 (0.3) 1.43 (0.54-3.75) or pulmonary embolusAtrial fibrillation 36 (1.5) 40 (1.7) 0.93 (0.59-1.46) * Only theinitial event was counted in the analyses of time to first event for theprimary composite end point and for the secondary composite end point.In the component analysis, all events (first and subsequent) werecounted separately. † The log-rank test and the multivariable Coxproportional-hazards model (including age, history of diabetes, previouscoronary revascularization, and previous heart failure yielded similar Pvalues. ‡ The secondary composite end point included death fromcardiovascular causes, resuscitated cardiac arrest, myocardialinfarction, and stroke.

The secondary efficacy end point consisting of a composite of death fromcardiovascular causes, cardiac arrest, myocardial infarction, or strokeoccurred in 4.7% of the patients in the colchicine group and in 5.5% ofthose in the placebo group (hazard ratio, 0.85; 95% CI, 0.66 to 1.10).Data on the primary, secondary, and exploratory efficacy end points areprovided in Table 13. Two patients had a first positively adjudicatedevent of urgent hospitalization for angina leading to coronaryrevascularization within 14 days after randomization. The median time tothis clinical end point was 258 days.

Efficacy results in prespecified subgroups are shown in Table 14. Thetotal number of primary end-point events (first and recurrent) was 154in the colchicine group and 223 in the placebo group, over periods of52,949 and 53,060 patient-months of follow-up, respectively. Thus, theprimary end-point event rates per 100 patient-months were 0.29 in thecolchicine group and 0.42 in the placebo group (rate ratio, 0.66; 95%CI, 0.51 to 0.86) (Table 15).

TABLE 14 Primary Efficacy Composite Endpoint in Prespecified Subgroups†.Colchicine Placebo Hazard ratio (95% CI) Subgroup no. of patients withevent/total no. of patients (%) All patients 131/2366 (5.5%) 170/2379(7.1%) 0.77 (0.61-0.96) Smoking Non-smoker 47/787 (6.0%) 52/797 (6.5%)0.90 (0.61; 1.34) Previous smoker 46/871 (5.3%) 77/872 (8.8%) 0.59(0.41; 0.85) Active smoker 38/708 (5.4%) 41/708 (5.8%) 0.93 (0.60; 1.44)History of diabetes Yes 40/462 (8.7%) 65/497 (13.1%) 0.65 (0.44; 0.96)No 91/1904 (4.8%) 105/1882 (5.6%) 0.85 (0.64; 1.13) History ofhypertension Yes 83/1185 (7.0%) 112/1236 (9.1%) 0.76 (0.57; 1.01) No48/1181 (4.1%) 58/1143 (5.1%) 0.80 (0.54; 1.17) Prior MI Yes 46/370(12.4%) 47/397 (11.8%) 1.05 (0.70; 1.58) No 85/1996 (4.3%) 123/1982(6.2%) 0.68 (0.51; 0.89) Prior PCI or CABG Yes 48/419 (11.5%) 57/447(12.8%) 0.91 (0.62; 1.34) No 83/1947 (4.3%) 113/1932 (5.8%) 0.72 (0.54;0.95) Prior stroke or TIA Yes 8/55 (14.5%) 9/67 (13.4%) 1.09 (0.42;2.82) No 123/2311 (5.3%) 161/2312 (7.0%) 0.76 (0.60; 0.96) Sex‡ Male94/1894 (5.0%) 135/1942 (7.0%) 0.70 (0.54; 0.91) Female 37/472 (7.8%)35/437 (8.0%) 0.99 (0.63; 1.58) White blood cell count¶ Below median41/660 (6.2%) 46/637 (7.2%) 0.85 (0.56; 1.29) Above median 34/637 (5.3%)44/664 (6.6%) 0.80 (0.51; 1.25) CABG denotes coronary artery bypassgraft, MI myocardial infarction, PCI percutaneous coronary intervention,and TIA transient ischemic attack. †The final amendment to thestatistical analysis plan, which listed the subgroups of interest, wasapproved on Aug. 28, 2019 and unblinding occurred on Aug. 29, 2019. ‡Thehazard ratio for the primary endpoint was 0.70 (0.52; 0.93) in men and0.81 (0.47; 1.41) in women in the per-protocol population.

The median value for total white blood cell count was 8.64×10³/μL.

TABLE 15 Total (First and Recurrent) Primary Endpoint Events. TotalPrimary Colchicine Placebo Endpoint Events (N = 2366) (N = 2379) Numberof primary 0 2235 2209 endpoint events per 1 111 132 patient 2 18 26 3 19 4 1 3 Total number of primary 154 223 endpoint events Total follow-upmonths 52949 53060 Rate of primary endpoint 0.29 0.42 events per 100patient-months Hazard Ratio or Rate Ratio (95% CI) Negative binomialmodel† 0.66 (0.51; 0.86) Andersen-Gill models‡ 0.69 (0.54; 0.88) WLWmodel¶ 1^(st) Event 0.77 (0.61; 0.96) 2^(nd) Event 0.73 (0.48; 1.11)3^(rd) Event 0.64 (0.37; 1.10) Average 0.77 (0.61; 0.96) WLW denotesWei-Lin-Weissfeld method. †The negative binomial regression model wasused to calculate marginal rate ratio. ‡The Andersen-Gill model was usedwith a robust variance estimator (sandwich estimator) to calculatehazard ratio.

Regarding Table 15, the Wei-Lin-Weissfeld marginal model was used tocalculate hazard ratios for the time to the first, second and thirdevent as well as the weighted average of these hazard ratios. To accountfor the occurrence of multiple primary endpoint events within patients,recurrent event analyses were undertaken using three statisticalapproaches as there is no strong consensus as to which method ispreferable. First, a negative binomial regression model was used withthe number of events as the outcome and the length of follow-up time inmonths as an offset term (Hansson G K. Inflammation, atherosclerosis,and coronary artery disease. N Engl J Med 2005; 352:1685-95). Marginalrate ratio was provided, along with 95% confidence interval. TheAndersen and Gill model (Ridker P M, et al., Antiinflammatory therapywith canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31) with a robust variance estimator (Ridker P M et al.,Low-dose methotrexate for the prevention of atherosclerotic events. NEngl J Med 2019; 380:752-62; and Ravelli R B et al., Insight intotubulin regulation from a complex with colchicine and a stathmin-likedomain. Nature 2004; 428:198-202) was utilized to account for thedependency of within-patient events based on a gap-time approachconsidering the time since a previous event. The Andersen-Gill model isa simple extension of the Cox model based on all events of all patientsand estimates a hazard ratio assuming that the instantaneous risk ofexperiencing an event is the same irrespective of whether previousevents occurred. Results from these two models are often similar (PericoN et al., Colchicine interferes with L-selectin and leukocytefunction-associated antigen-1 expression on human T lymphocytes andinhibits T cell activation. J Am Soc Nephrol 1996; 7:594-601; and Pope RM and Tschopp J, The role of interleukin-1 and the inflammasome in gout:implications for therapy. Arthritis Rheum 2007; 56:3183-8). Finally, anapproach based on the Wei, Lin and Weissfeld marginal model wasconducted whereby times from randomization to first, second andsubsequent event were modeled with a Cox proportional hazards model thatused a covariance matrix estimate for the regression coefficients thataccounted for the possible intra-patient correlation (Cerquaglia C etal., Pharmacological and clinical basis of treatment of FamilialMediterranean Fever (FMF) with colchicine or analogues: an update. CurrDrug Targets Inflamm Allergy 2005; 4:117-24; Imazio M et al., Colchicinein addition to conventional therapy for acute pericarditis: results ofthe COlchicine for acute PEricarditis (COPE) trial. Circulation 2005;112:2012-6; and Nidorf S M et al., Low-dose colchicine for secondaryprevention of cardiovascular disease. J Am Coll Cardiol 2013;61:404-10). This approach assumes that all patients are at risk for anyevent since randomization. Marginal hazard ratios for a kth event (i.e.based on time from randomization to kth event), as well as a weightedaverage of these hazard ratios, were provided along with 95% confidenceintervals. It has been argued that this approach preserves therandomization and permits valid treatment effect estimation (Fine J Pand Gray R J, A proportional hazards model for the subdistribution of acompeting risk. J Am Stat Assoc 1999; 94:496-509).

Biomarkers of Inflammation

High-sensitivity C-reactive protein was measured in a subgroup of only207 patients at the time of randomization and 6 months later, and themedian concentration at trial entry was 4.28 mg per liter. The baselinecharacteristics of these patients were similar to those of the overallpopulation (Table 16), but the small and selected subgroup with thesedata limits the interpretation of these analyses. The adjusted geometricmean percent changes in the high-sensitivity C-reactive protein level at6 months after myocardial infarction were −70.0% in the colchicine groupand −66.6% in the placebo group, and the placebo-adjusted geometric meanpercent change was −10.1% percentage points in the colchicine group (95%CI, −28.6 to 13.4) (Table 17).

TABLE 16 Characteristics of the Trial Patients with hs-CRP data values.Characteristic Colchicine (N = 99) Placebo (N = 108) Age - years 62.1 ±9.7 61.2 ± 10.2 Female sex - no. (%) 18 (18.2%) 14 (13.0%) Caucasian -no. (%) 91 (93.8%) 89 (89.0%) Body-mass index 28.8 ± 4.5 29.1 ± 4.2(kg/m²) Smoking - no. (%) 20 (20.2%) 20 (18.5%) Hypertension - no. (%)44 (44.4%) 62 (57.4%) Diabetes - no. (%) 12 (12.1%) 15 (13.9%) PriorMI - no. (%) 14 (14.1%) 16 (14.8%) Prior PCI - no. (%) 24 (24.2%) 21(19.4%) Prior CABG - no. (%) 4 (4.0%) 6 (5.6%) Prior heart failure - no.(%) 4 (4.0%) 1 (0.9%) Prior stroke/TIA - no. (%) 1 (1.0%) 2 (1.9%) IndexMI to 17.0 ± 9.2 15.8 ± 9.8 randomization - days PCI for index MI - no.(%) 93 (93.9%) 104 (96.3%) Aspirin use - no. (%) 98 (99.0%) 106 (98.1%)Other anti-platelet 98 (99.0%) 108 (100%) agent - no. (%) Statin use -no. (%) 99 (100%) 107 (99.1%) Beta-blocker - no. (%) 83 (83.8%) 86(79.6%) CABG denotes coronary artery bypass graft surgery, MI myocardialinfarction, PCI percutaneous coronary intervention, and TIA transientischemic attack.

TABLE 17 Biomarkers of Inflammation. Biomarker Colchicine Placebo Hs-Creactive protein (mg/L) N = 99 N = 108 Randomization, geometric mean(IQR)† 4.27 (2.12, 7.22) 5.09 (2.45, 11.96) 6 months, geometric mean(IQR) 1.37 (0.75, 2.13) 1.60 (0.90, 2.65) Adjusted GM percent change(95% CI)‡ −70.0 (−74.6, −64.5) −66.6 (−71.5, −60.8) Placebo-adjusted GMpercent change (95% CI)¶ −10.1 (−28.6, 13.4) — N = 992 N = 980 Totalwhite blood cell count (10³/μL) Randomization, geometric mean (IQR)†8.54 (7.10, 10.40) 8.63 (7.20, 10.70) 12 months, geometric mean (IQR)6.95 (5.99, 8.30) 7.03 (5.96, 8.48) Adjusted GM percent change (95% CI)‡−18.81 (−20.12, −17.47) −19.02 (−20.46, −17.55) Placebo-adjusted GMpercent change (95% CI)¶ 0.26 (−2.15, 2.72) — Circulating lymphocytes(10³/μL) Randomization, geometric mean (IQR)† 1.79 (1.40, 2.40) 1.79(1.42, 2.46) 12 months, geometric mean (IQR) 1.83 (1.50, 2.44) 1.82(1.50, 2.44) Adjusted GM percent change (95% CI)‡ 1.80 (−0.46, 4.11)0.69 (−1.54, 2.98) Placebo-adjusted GM percent change (95% CI)¶ 1.10(−2.06, 4.36) — Circulating neutrophils (10³/μL) Randomization,geometric mean (IQR)† 5.45 (4.36, 7.15) 5.47 (4.30, 7.46) 12 months,geometric mean (IQR) 3.95 (3.27, 5.08) 3.99 (3.34, 5.20) Adjusted GMpercent change (95% CI)‡ −27.63 (−29.48, −25.73) −27.95 (−29.91, −25.93)Placebo-adjusted GM percent change (95% CI)¶ 0.45 (−3.28, 4.32) — GMdenotes geometric mean, HS high-sensitivity, and IQR inter-quartilerange. †The geometric mean was obtained by exponentiating the mean oflog-transformed data. ‡The adjusted geometric mean percent change wasobtained by exponentiating the adjusted mean from the analysis ofcovariance model (based on log-transformed data), then subtracting 1 andmultiplying by 100. The bounds of the 95% confidence intervals wereobtained similarly.

In Table 17, the placebo-adjusted geometric mean percent change wasobtained by exponentiating the adjusted mean difference between groupsfrom the analysis of covariance model (based on log-transformed data),then subtracting 1 and multiplying by 100.

In addition, the C-reactive protein biomarker sub-study was implementedfollowing a protocol amendment and was optional for sites and forpatients; 34 sites accepted to participate in this substudy. There were213 and 208 patients who provided blood samples at baseline and 6months, respectively. Paired baseline and 6-month hs-CRP values wereavailable in 207 patients. Clinically available white blood cell countswere obtained from 2598 patients at baseline and 1998 patients at 12months, and paired baseline and 12-month values were available in 1972patients. Statistical analysis was conducted on the patients whoprovided both baseline and follow-up data and as these were exploratoryanalyses, no missing data was imputed.

Information about white-cell counts at baseline and at the 12-monthfollow-up were also available for a relatively small subgroup of 1972patients. The adjusted geometric mean percent changes from baseline to 1year in the total white-cell count were −18.8% in the colchicine groupand −19.0% in the placebo group, with no significant difference betweengroups (0.3% percentage points; 95% CI, −2.2 to 2.7).

Safety and Adverse Events

The incidence of adverse events that were considered to be related totrial drug was 16.0% in the colchicine group and 15.8% in the placebogroup, and the overall incidence of serious adverse events was 16.4% and17.2%, respectively (Table 18).

TABLE 18 Adverse Events (Safety Population) Colchicine Placebo (N =2330) (N = 2346) Event number of patients (percent) P Value Any relatedadverse event† 372 (16.0) 371 (15.8) 0.89 Any serious adverse event‡ 383(16.4) 404 (17.2) 0.47 Gastrointestinal 408 (17.5) 414 (17.6) 0.90adverse event Gastrointestinal serious 46 (2.0 ) 36 (1.5) 0.25 adverseevent Diarrhea adverse event 225 (9.7) 208 (8.9) 0.35 Nausea adverseevent 43 (1.8) 24 (1.0) 0.02 Flatulence adverse event 15 (0.6) 5 (0.2)0.02 Gastrointestinal hemorrhage 7 (0.3) 5 (0.2) 0.56 Infection serious51 (2.2) 38 (1.6) 0.15 adverse event Pneumonia serious 21 (0.9) 9 (0.4)0.03 adverse event Septic shock serious 2 (0.1) 2 (0.1) 0.99 adverseevent Hospitalization for 25 (1.1) 17 (0.7) 0.21 heart failure Cancer§43 (1.8) 46 (2.0) 0.77 Anemia 14 (0.6) 10 (0.4) 0.40 Leukopenia 2 (0.1)3 (0.1) 0.66 Thrombocytopenia 3 (0.1) 7 (0.3) 0.21 * The safetypopulation was defined as patients who took at least one dose ofcolchicine or placebo. All serious adverse events were recorded, and theonly other adverse events recorded were those that were related to thegastrointestinal system, events that were judged by the investigator tobe related to colchicine or placebo, or laboratory abnormalities thatwere judged by the investigator to be clinically significant. This tablelists serious adverse events that were present in more than 2% of thepatients in either trial group, adverse events that were considered tobe related to colchicine or placebo in more than 5% of the patients ineither trial group, and any other safely events of special interest.Chi-square tests were conducted to compare the incidence of adverseevents between the trial groups. †These adverse events were consideredto be related to colchicine or placebo by the physician in charge of theparticipant. ‡There was one serious adverse event of myopathy, which wasattributed to high-dose statin therapy (rosuvastatin at a dose of 40 mgdaily) by the local investigator and academic sponsor, in a man of shortstature (165 cm, 68 kg) with normal renal function in the colchicinegroup who had received colchicine for 8 days 3 months before the adverseevent. §Cancers, excluding nonmelanoma skin cancers, occurred in 42patients (1.8%) in the colchicine group and in 44 (1.9%) in the placebogroup.

At least one gastrointestinal adverse event during the double-blindperiod occurred in 17.5% of the patients in the colchicine group, ascompared with 17.6% of those in the placebo group. Diarrhea was reportedin 9.7% of the patients in the colchicine group and in 8.9% of those inthe placebo group (P=0.35), and nausea was more common in the colchicinegroup than in the placebo group (1.8% vs. 1.0%, P=0.02). Pneumonia wasreported as a serious adverse event in 0.9% of the patients in thecolchicine group, as compared with 0.4% of those in the placebo group(P=0.03).

In COLCOT, the risk of the primary composite efficacy end point of deathfrom cardiovascular causes, resuscitated cardiac arrest, myocardialinfarction, stroke, or urgent hospitalization for angina leading tocoronary revascularization, as assessed in a time-to-event analysis, wassignificantly lower among the patients who were randomly assigned toreceive 0.5 mg of colchicine once daily than among those who receivedplacebo. This result was due predominantly to a lower incidence ofstrokes and urgent hospitalizations for angina leading to coronaryrevascularization.

These results were observed against a background of appropriatemedications, which included aspirin, a different antiplatelet agent, anda statin in 98 to 99% of the patients. In addition, percutaneouscoronary intervention was performed in 93% of the patients for theirindex myocardial infarction. The benefits of colchicine with regard tocardiovascular end points in COLCOT were at least as large as those ofcanakinumab in CANTOS (Ridker P M et al., Antiinflammatory therapy withcanakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31). In the small subgroup of patients with available data, alarge (>65%) reduction in the C-reactive protein level occurred over thefirst 6 months after myocardial infarction in both trial groups inCOLCOT, but the difference between the changes in the groups was notsignificant. These findings must be interpreted cautiously given thatthis was a small subgroup that was not randomly selected from the fulltrial sample. A similar observation was made with white-cell counts. Thedifferent patient populations involved in the two trials—early aftermyocardial infarction in COLCOT and stable coronary disease in CANTOS—may also have affected the relationship between biomarkers ofinflammation and the effects of treatments on ischemic end points.

The known benefits of colchicine in the treatment of pericarditis werenot at play in COLCOT.

Postinfarction pericarditis typically occurs within the first few daysafter the injury, whereas the mean time from the index myocardialinfarction to randomization was 13.5 days. There were only two patientswith a first positively adjudicated event of urgent hospitalization forangina leading to coronary revascularization within 14 days afterrandomization, and the median time to this clinical end point was 258days.

The most common adverse events observed were gastrointestinal. Diarrheawas reported in 9.7% of the patients in the colchicine group and in 8.9%of those in the placebo group, and nausea occurred in 1.8% and 1.0%,respectively. Infection as a serious adverse event was more frequent inthe colchicine group than in the placebo group (in 2.2% vs. 1.6% of thepatients), and pneumonia as a serious adverse event was also morefrequent in the colchicine group (0.9% vs. 0.4%). These differences inthe incidence of infections could be due to the play of chance or couldreflect altered immunologic responses.

In contrast to canakinumab (Ridker P M et al., Antiinflammatory therapywith canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31), colchicine did not increase the incidence of septic shockin our trial. Infections have previously been described in patients whohave attempted suicide by taking an overdose of colchicine (Kocak Z etal., Colchicine intoxication and infection risk: a case report. J ClinPharm Ther 2008; 33:451-2). There was no serious adverse event ofmyopathy linked to colchicine despite the use of statins in 99% of thepatients in the trial.

In conclusion, among patients with a recent myocardial infarction,colchicine at a dose of 0.5 mg daily led to a significantly lowerpercentage of patients with ischemic cardiovascular events than placebo.

Other Embodiments

While the invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications and this application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure that come within known or customary practice withinthe art to which the invention pertains and may be applied to theessential features hereinbefore set forth, and follows in the scope ofthe claims.

Some embodiments of the invention are within the following numberedparagraphs.

1. A method of treating a patient after having a myocardial infarction(MI), the method comprising initiating the administration of colchicineat a daily low dose to the patent within about 3 days of the MI.

2. A method of treating a patient after having a myocardial infarction(MI), the method comprising initiating the administration of colchicineat a daily low dose to the patient within about 4 days of the MI.

3. The method paragraph 1 or 2, wherein percutaneous coronaryintervention was performed for treating the patient's MI.

4. The method of any one of paragraphs 1-3, wherein the patient wasprescribed a medication.

5. The method according to paragraph 4, wherein the medication is anantiplatelet agent.

6. The method according to paragraph 4, wherein the medication isaspirin.

7. The method according to paragraph 4, wherein the medication is astatin.

8. The method according to any one of paragraphs 1-7, wherein thepatient is at a lower risk of a cardiovascular event, relative to apatient not being administered colchicine.

9. The method according to paragraph 8, wherein the cardiovascular eventis an ischemic cardiovascular event.

10. The method according to paragraph 8, wherein the cardiovascularevent is cardiovascular death, resuscitated cardiac arrest, myocardialinfarction, stroke, or urgent hospitalization for angina requiringcoronary revascularization.

11. The method according to any one of paragraphs 1-10, wherein thepatient has atherosclerotic coronary artery disease.

12. A method of reducing the risk of a stroke in a patient after havingan MI, the method comprising initiating the administration of colchicineat a daily low dose to the patient within about 30 days of the MI.

13. The method according to paragraph 12, wherein the method comprisesadministering colchicine within 4-7 days of the MI.

14. The method according to paragraph 12, wherein the method comprisesadministering colchicine within 3 days of the MI.

16. The method according to any one of paragraphs 1-15, wherein theadministration of colchicine is initiated upon assessment in (a) anemergency department (ED), (b) the hospital, or (c) a medical officesetting.

17. The method according to any one of paragraphs 1-16, wherein thecolchicine is in the form of a tablet.

18. The method of paragraph 17, wherein the tablet is coated.

19. The method of paragraph 18, wherein the tablet is film-coated.

20. The method according to any one of paragraphs 1-19, wherein thecolchicine is administered at 0.3 to 0.7 mg.

21. The method according to any one of paragraphs 1-20, wherein thecolchicine is administered at 0.4 to 0.6 mg.

22. The method according to paragraph 21, wherein the colchicine isadministered at about 0.5 mg.

23. The method according to any one of paragraph 1-22, wherein thecolchicine is administered once, twice or three times a day.

24. The method according to paragraph 23, wherein the colchicine isadministered once per day.

25. The method of any one of paragraphs 1-24, wherein the colchicine isadministered without pre-loading the patient with colchicine.

26. The method of any one of paragraphs 1-25, wherein the patient is anadult human.

Other embodiments are within the claims.

What is claimed is:
 1. A method of treating a patient after having amyocardial infarction (MI), the method comprising initiating theadministration of colchicine at a daily low dose to the patient withinabout 3 days of the MI.
 2. The method according to claim 1, whereinpercutaneous coronary intervention was performed for treating thepatient's MI.
 3. The method according to claim 1, wherein the patientwas prescribed a medication.
 4. The method according to claim 3, whereinthe medication is an antiplatelet agent.
 5. The method according toclaim 3, wherein the medication is aspirin.
 6. The method according toclaim 3, wherein the medication is a statin.
 7. The method according toclaim 1, wherein the patient is at a lower risk of a cardiovascularevent, relative to a patient not being administered colchicine.
 8. Themethod according to claim 7, wherein the cardiovascular event is anischemic cardiovascular event.
 9. The method according to claim 7,wherein the cardiovascular event is resuscitated cardiac arrest.
 10. Themethod according to claim 7, wherein the cardiovascular event ismyocardial infarction.
 11. The method according to claim 7, wherein thecardiovascular event is stroke.
 12. The method according to claim 7,wherein the cardiovascular event is urgent hospitalization for anginarequiring coronary revascularization.
 13. The method according to claim1, wherein the patient has atherosclerotic coronary artery disease. 14.The method according to claim 1, wherein the administration ofcolchicine is initiated upon assessment in (a) an emergency department(ED), (b) the hospital, or (c) a medical office setting.
 15. The methodaccording to claim 1, wherein the colchicine is in the form of a tablet.16. The method of claim 15, wherein the tablet is coated.
 17. The methodof claim 16, wherein the tablet is film-coated.
 18. The method accordingto claim 1, wherein the colchicine is administered at 0.3 to 0.7 mg. 19.The method according to claim 18, wherein the colchicine is administeredat 0.4 to 0.6 mg.
 20. The method according to claim 16, wherein thecolchicine is administered at 0.5 mg.
 21. The method according to claim9, wherein the colchicine is administered at 0.5 mg.
 22. The methodaccording to claim 10, wherein the colchicine is administered at 0.5 mg.23. The method according to claim 11, wherein the colchicine isadministered at 0.5 mg.
 24. The method according to claim 12, whereinthe colchicine is administered at 0.5 mg.
 25. The method according toclaim 1, wherein the colchicine is administered once, twice or threetimes a day.
 26. The method according to claim 25, wherein thecolchicine is administered once per day.
 27. The method according toclaim 1, wherein the colchicine is administered without pre-loading thepatient with colchicine.
 28. The method according to claim 1, whereinthe patient is an adult human.
 29. A method of reducing the risk of astroke in a patient after having an MI, the method comprising initiatingthe administration of colchicine at a daily low dose to the patientwithin about 30 days of an MI.
 30. The method according to claim 29,wherein the method comprises administering colchicine within 4 to 7 daysof the MI.